Novel Heterocyclic Derivatives as Modulators of Kinase Activity

ABSTRACT

The invention provides novel imidazol-piperidinyl derivatives of the formula (I) 
     
       
         
         
             
             
         
       
     
     in which R 1 , R 2 , W, X 1 , X 2 , X 3 , X 4  and n have the meanings indicated in formula I, and their manufacture and use for the treatment of hyperproliferative diseases, such as cancer.

FIELD OF THE INVENTION

The invention relates to a series of heterocyclic compounds that areuseful in the treatment of hyperproliferative diseases, such as cancer,in mammals. Also encompassed by the present invention is the use of suchcompounds in the treatment of hyperproliferative diseases in mammals,especially humans, and pharmaceutical compositions containing suchcompounds.

BACKGROUND

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).

Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

Protein kinase 70S6K, the 70 kDa ribosomal protein kinase p70S6K (alsoknown as SK6, p70/p85 S6 kinase, p70/p85 ribosomal S6 kinase andpp70S6K), is a member of the AGC subfamily of protein kinases. p70S6K isa serine-threonine kinase that is a component of thephosphatidylinositol 3 kinase (PI3K)/AKT pathway. p70S6K is downstreamof PI3K, and activation occurs through phosphorylation at a number ofsites in response to numerous mitogens, hormones and growth factors.p70S6K activity is also under the control of a mTOR-containing complex(TORC1) since rapamycin acts to inhibit p70S6K activity. p70S6K isregulated by PI3K downstream targets AKT and PKCζ. Akt directlyphosphorylates and inactivates TSC2, thereby activating mTOR. Inaddition, studies with mutant alleles of p70S6K that inhibited byWortmannin but not by rapamycin suggest that the PI3K pathway canexhibit effects on p70S6K independent of the regulation of mTORactivity.

The enzyme p70S6K modulates protein synthesis by phosphorylation of theS6 ribosomal protein. S6 phosphorylation correlates with increasedtranslation of mRNAs encoding components of the translational apparatus,including ribosomal proteins and translational elongation factors whoseincreased expression is essential for cell growth and proliferation.These mRNAs contain an oligopyrimidime tract at their 5′ transcriptionalstart (termed 5′TOP), which has been shown to be essential for theirregulation at the translational level.

In addition to its involvement in translation, p70S6K activation hasalso been implicated in cell cycle control, neuronal celldifferentiation, regulation of cell motility and a cellular responsethat is important in tumor metastases, the immune response and tissuerepair. Antibodies to p70S6K abolish the mitogenic response driven entryof rat fibroblasts into S phase, indication that p70S6K function isessential for the progression from G1 to S phase in the cell cycle.Furthermore, inhibition of cell cycle proliferation at the G1 to S phaseof the cell cycle by rapamycin has been identified as a consequence ofinhibition of the production of the hyperphosphorylated, activated formof p70S6K.

A role for p70S6K in tumor cell proliferation and protection of cellsfrom apoptosis is supported based on its participation in growth factorreceptor signal transduction, overexpression and activation in tumortissues. For example, Northern and Western analyses revealed thatamplification of the PS6K gene was accompanied by correspondingincreases in mRNA and protein expression, respectively (Cancer Res.(1999) 59: 1408-11-Localization of PS6K to Chromosomal Region 17q23 andDetermination of Its Amplification in Breast Cancer).

Chromosome 17q23 is amplified in up to 20% of primary breast tumors, in87% of breast tumors containing BRCA2 mutations and in 50% of tumorscontaining BRCA1 mutations, as well as other cancer types such aspancreatic, bladder and neuroblastoma (see M. Barlund, O. Monni, J.Kononen, R. Cornelison, J. Torhorst, G. Sauter, O.-P. Kallioniemi andKallioniemi A., Cancer Res., 2000, 60:5340-5346). It has been shown that17q23 amplifications in breast cancer involve the PAT1, RAD51C, PS6K,and SIGMA1B genes (Cancer Res. (2000): 60, pp. 5371-5375).

The p70S6K gene has been identified as a target of amplification andoverexpression in this region, and statistically significant associationbetween amplification and poor prognosis has been observed. Clinicalinhibition of p70S6K activation was observed in renal carcinoma patientstreated with CCI-779 (rapamycin ester), an inhibitor of the upstreamkinase mTOR. A significant linear association between diseaseprogression and inhibition of p70S6K activity was reported. In responseto energy stress, the tumor suppressor LKB1 activates AMPK whichphosphorylates the TSC1/2 complex and enables it to inactivate themTOR/p70S6K pathway. Mutations in LKB1 cause Peutz-Jeghers syndrome(PJS), where patients with PJS are 15 times more likely to developcancer than the general population. In addition, 1/3 of lungadenocarcinomas harbor inactivating LKB1 mutations. P70S6K has beenimplicated in metabolic diseases and disorders. It was reported that theabsence of p70S6K protects against age- and diet-induced obesity whileenhancing insulin sensitivity. A role for p70S6K in metabolic diseasesand disorders such as obesity, diabetes, metabolic syndrome, insulinresistance, hyperglycemia, hyperaminoacidemia, and hyperlipidmia issupported based upon the findings.

Compounds described as suitable for p70S6K inhibition are disclosed inWO 03/064397, WO 04/092154, WO 05/054237, WO 05/056014, WO 05/033086, WO05/117909, WO 05/039506, WO 06/120573, WO 06/136821, WO 06/071819, WO06/131835, WO 08/140947, WO 10/056563, WO 10/093419, WO 12/013282, WO12/016001 and WO 12/069146.

SUMMARY OF THE INVENTION

The invention provides for compounds of formula I which are useful totreat p70S6K related disorders.

DESCRIPTION OF THE INVENTION

It is the object of the present invention to provide novel compoundsthat modulate kinase activity. This protein kinase modulation includes,but is not limited to, p70S6K inhibition and Akt inhibition useful inthe treatment of hyperproliferative diseases, especially those relatedto the hyperactivity of the above mentioned protein kinases, such ascancer in mammals, with superior pharmacological properties both withrespect to their activities as well as their solubility, metabolicclearance and bioavailability characteristics.

As a result, this invention provides novel heterocyclic derivatives andpharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof, that are kinase inhibitors and useful in the treatment of theabove mentioned diseases.

The invention relates to compounds of the formula (I)

and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof, wherein:

-   X¹ is N or CH,-   X² is CH₂ or NH,-   X³ is CH₂ or CO,-   X⁴ is O, CH₂ or NH,-   W is N or CH,-   R¹ is Ar or Het,-   R² is [C(R³)₂]_(p)Het¹ or [C(R³)₂]_(p)N(R³)₂,-   R³ is H or alkyl with 1, 2, 3, or 4 C-atoms, which is optionally    substituted;-   Ar is phenyl which is unsubstituted or mono-, di- or trisubstituted    by Hal, A, phenyl, CON(R³)₂, COOR³, NHCOA, NHSO₂A, CHO, COA,    SO₂N(R³)₂, SO₂A, [C(R³)₂]_(p)OR³, [C(R³)₂]_(p)N(R³)₂ and/or    [C(R³)₂]_(p)CN,-   Het is furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,    isoxazolyl, oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl,    pyrimidyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl,    benzimidazolyl, indazolyl or quinolyl, which is unsubstituted or    mono-, di- or trisubstituted by Hal, A, [C(R³)₂]_(p)OR³,    [C(R³)₂]_(p)—N(R³)₂, NO₂, CN, [C(R³)₂]_(p)COOR³, CON(R³)₂, NR³COA,    NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A and/or O[C(R³)₂]_(q)N(R³)₂,-   Het¹ is dihydropyrrolyl, pyrrolidinyl, azetidinyl, oxetanyl,    tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl,    tetrahydrofuranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl,    azepanyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl,    [1,3]dioxolanyl, tetrahydropyranyl, pyridyl or piperazinyl, which is    unsubstituted or mono- or disubstituted by A,-   A is unbranched or branched alkyl with 1-10 C-atoms, wherein one or    two non-adjacent CH- and/or CH₂-groups may be replaced by N-, O-    and/or S-atoms and wherein 1-7 H-atoms may be replaced by F or Cl,-   Hal is F, Cl, Br or I,-   each m is independently 0, 1 or 2,-   each n is independently 0, 1 or 2,-   each p is independently 0, 1, 2, 3 or 4,-   each q is independently 2, 3 or 4.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of these compounds.

The invention also relates to the solvates of the salts of the compoundsof formula I, e.g. the mono- or dihydrate of the hydrochloride.

Moreover, the invention relates to pharmaceutically acceptablederivatives of compounds of formula I.

The term solvates of the compounds is taken to mean adductions of inertsolvent molecules onto the compounds which form owing to their mutualattractive force. Solvates are, for example, mono- or dihydrates oralcoholates.

The term pharmaceutically acceptable derivatives is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound of formula I that can hydrolyze, oxidize, orotherwise react under biological conditions (in vitro or in vivo) toprovide an active compound, particularly a compound of formula I.Examples of prodrugs include, but are not limited to, derivatives andmetabolites of a compound of formula I that include biohydrolyzablemoieties such as biohydrolyzable amides, biohydrolyzable esters,biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzableureides, and biohydrolyzable phosphate analogues. In certainembodiments, prodrugs of compounds with carboxyl functional groups arethe lower alkyl esters of the carboxylic acid. The carboxylate estersare conveniently formed by esterifying any of the carboxylic acidmoieties present on the molecule. Prodrugs can typically be preparedusing well-known methods, such as those described by Burger's MedicinalChemistry and Drug Discovery 6th ed. (Donald J. Abraham ed., 2001,Wiley) and Design and Application of Prodrugs (H. Bundgaard ed., 1985,Harwood Academic Publishers Gmfh).

The expression “effective amount” denotes the amount of a medicament orof a pharmaceutical active ingredient which causes in a tissue, system,animal or human a biological or medical response which is sought ordesired, for example, by a researcher or physician.

In addition, the expression “therapeutically effective amount” denotesan amount which, compared with a corresponding subject who has notreceived this amount, has the following consequence:

improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder.

The expression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The invention also relates to the use of mixtures of the compounds ofthe formula I, for example mixtures of two diastereomers, for example inthe ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, e.g., keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,e.g., the keto or the enol form, are claimed separately and together asmixtures in any ratio. The same applies for stereoisomers, e.g.,enantiomers, cis/trans isomers, conformers and the like. If desired,isomers can be separated by methods well known in the art, e.g. byliquid chromatography. The same applies for enantiomers, e.g., by usingchiral stationary phases. Additionally, enantiomers may be isolated byconverting them into diastereomers, i.e., coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials

The term “substituted” preferably relates to the substitution by theabove-mentioned substituents, where a plurality of different degrees ofsubstitution is possible, unless indicated otherwise.

All physiologically acceptable salts, derivatives, solvates, solvates ofsalts, and stereoisomers of these compounds, including mixtures thereofin all ratios, are also in accordance with the invention.

The invention relates to the compounds of the formula I and saltsthereof and to a process for the preparation of compounds of the formulaI and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof, characterised in that

-   a) a compound of the formula (II)

-   -   in which X¹, X², X³, X⁴ and n have the meanings indicated in        formula I,        is reacted with a compound of the formula (III)

-   -   in which W, R¹ and R² have the meanings indicated in formula I,        or

-   b) for the preparation of compounds of the formula I, wherein X³ is    CO and X⁴ is NH,    -   a compound of the formula (IV)

-   -   -   in which R¹, R², W, X¹, X² and n have the meanings indicated            in formula I, and A′ is alkyl with 1, 2, 3 or 4 C-atoms,

    -   is cyclised,        and/or        a base or acid of the formula I is converted into one of its        salts.

Above and below, the radicals R¹, R², W, X¹, X², X³, X⁴ and n have themeanings indicated for the formula I, unless expressly stated otherwise.

“A” denotes alkyl, this is unbranched (linear) or branched, and has 1,2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. “A” preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

“A” very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl. Moreover, “A” denotes e.g. CH₂OCH₃, CH₂CH₂OH,OCH₂CH₂NH₂, CH₂NHCH₂ or NHCH₂CH₃.

Cyc preferably denotes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylor cycloheptyl.

R¹ preferably denotes Ar.

R³ preferably denotes H or alkyl having 1, 2, 3 or 4 C atoms,particularly preferably H or methyl.

Ar denotes, for example, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-,m- or p-propyl-phenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert-butylphenyl, o-, m- or p-hydroxy-phenyl, o-, m- or p-nitrophenyl,o-, m- or p-aminophenyl, o-, m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-methoxyphenyl, o-, m- orp-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- orp-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl, o-, m-or p-cyano-phenyl, o-, m- or p-carboxyphenyl, o-, m- orp-methoxycarbonylphenyl, o-, m- or p-formylphenyl, o-, m- orp-acetylphenyl, o-, m- or p-aminosulfonylphenyl, o-, m- orp-[2-(morpholin-4-yl)ethoxy]phenyl, o-, m- orp-[3-(N,N-diethylamino)propoxy]phenyl, furthermore preferably 2,3-,2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-,2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro- or2-amino-6-chlorophenyl, 2-nitro-4-N,N-dimethylamino- or3-nitro-4-N,N-dimethylaminophenyl, 2,3-diaminophenyl, 2,3,4-, 2,3,5-,2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Ar furthermore preferably denotes phenyl which is unsubstituted or mono-or disubstituted by Hal and/or A.

Ar particularly preferably denotes phenyl which is monosubstituted byCF₃, F or Cl.

Het preferably denotes pyridyl or pyrimidyl, which is unsubstituted ormonosubstituted by “A”.

Het¹ preferably denotes pyrrolidinyl, azetidinyl or piperidinyl.

Hal preferably denotes F, Cl or Br, but also I, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I may have one or more chiral centres andcan therefore occur in various stereoisomeric forms. The formula Iencompasses all these forms.

Accordingly, the invention relates, in particular, to the compounds ofthe formula I in which at least one of the said radicals has one of thepreferred meanings indicated above. Some preferred groups of compoundsmay be expressed by the following sub-formulae Ia to Ie, which conformto the formula I and in which the radicals not designated in greaterdetail have the meaning indicated for the formula I, but in which

-   in Ia R³ is H or methyl;-   in Ib Ar is phenyl which is unsubstituted or mono- or disubstituted    by Hal and/or A;-   in Ic Het is pyridyl or pyrimidyl, which is unsubstituted or    monosubstituted by A;-   in Id Het¹ is pyrrolidinyl, azetidinyl or piperidinyl;-   in Ie X¹ is N or CH,    -   X² is CH₂ or NH,    -   X³ is CH₂ or CO,    -   X⁴ is CH₂ or NH,    -   R¹ is Ar,    -   R² is [C(R³)₂]_(p)Het¹ or [C(R³)₂]_(p)N(R³)₂,    -   R³ is H or methyl,    -   Ar is phenyl which is unsubstituted or mono- or disubstituted by        Hal and/or A,    -   Het¹ is pyrrolidinyl, azetidinyl or piperidinyl,    -   A is unbranched or branched alkyl with 1-10 C-atoms, wherein one        or two non-adjacent CH- and/or CH₂-groups may be replaced by N-        and/or O-atoms and wherein 1-7 H-atoms may be replaced by        -   F or Cl,        -   or Cyc,    -   Cyc is cyclic alkyl with 3-7 C-atoms,    -   Hal is F, Cl, Br or I,    -   each n is independently 0 or 1,    -   each p is independently 0, 1, 2, 3 or 4;        and pharmaceutically acceptable salts, solvates, solvates of        salts, tautomers or stereoisomers, including mixtures thereof in        all ratios thereof.

In certain embodiments of any of the formulae presented herein, R¹ is

In certain embodiments of any of the formulae presented herein, R² is

In certain embodiments, of any of the formulae presented herein the ring

In certain embodiments, the invention provides a compound of formulaI-f:

and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof;wherein R¹ and R² are as defined above.

In certain embodiments, the invention provides a compound of formulaI-g:

and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof;wherein R¹ and R² are as defined above.

In certain embodiments, the invention provides a compound of formulaI-h:

and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof;wherein R¹ and R² are as defined above.

In certain embodiments, the invention provides a compound of formulaI-i:

and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof;wherein R¹ and R² are as defined above.

In certain embodiments, the invention provides a compound of formulaI-j:

and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof;wherein R¹ and R² are as defined above.

In certain embodiments, the invention provides a compound of formulaI-k:

and pharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof;wherein R¹ and R² are as defined above.

In certain embodiments of any of formulae I-f to I-k, R¹ is

In certain embodiments of any of formulae I-f to I-k, R² is

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise Use can alsobe made here of variants known per se which are not mentioned here ingreater detail.

The starting compounds of the formulae II and III are generally known.If they are novel, however, they can be prepared by methods known perse.

Compounds of the formula I can preferably be obtained by reacting acompound of the formula II with a compound of the formula III.

Moreover, compounds of the formula I can preferably be obtained bycyclizing a compound of the formula IV.

The reaction is generally carried out under conditions known to theskilled artisan and which are known and suitable for the said reaction.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about 0° and160°, normally between 20° and 150°, in particular between about 60° anda bout 140°.

The reaction is generally carried out in the presence of an acid-bindingagent, preferably an organic base, such as DIPEA, triethylamine,dimethylaniline, pyridine or quinoline.

The addition of an alkali or alkaline earth metal hydroxide, carbonateor bicarbonate or another salt of a weak acid of the alkali or alkalineearth metals, preferably of potassium, sodium, calcium or caesium, mayalso be favourable.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; alcohols, such as methanol, ethanol,isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether,ethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to DMF, DMSO orNMP.

Pharmaceutical Salts and Other Forms

The said compounds according to the invention can be used in their finalnon-salt form. On the other hand, the present invention also encompassesthe use of these compounds in the form of their pharmaceuticallyacceptable salts, which can be derived from various organic andinorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds of the formula Iare for the most part prepared by conventional methods. If the compoundof the formula I contains a carboxyl group, one of its suitable saltscan be formed by reacting the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as bariumhydroxide and calcium hydroxide; alkali metal alkoxides, for examplepotassium ethoxide and sodium propoxide; and various organic bases, suchas piperidine, diethanolamine and N-methylglutamine. The aluminium saltsof the compounds of the formula I are likewise included. In the case ofcertain compounds of the formula I, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds of the formula I include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprylate, chloride, chlorobenzoate, citrate,cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

Furthermore, the base salts of the compounds according to the inventioninclude aluminium, ammonium, calcium, copper, iron(III), iron(II),lithium, magnesium, manganese(III), manganese(II), potassium, sodium andzinc salts, but this is not intended to represent a restriction. Of theabove-mentioned salts, preference is given to ammonium; the alkali metalsalts sodium and potassium, and the alkaline earth metal salts calciumand magnesium. Salts of the compounds of the formula I which are derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary and tertiary amines, substituted amines, alsoincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchanger resins, for example arginine, betaine, caffeine,chloroprocaine, choline, N,N′-dibenzylethylenediamine (benzathine),dicyclohexylamine, diethanolamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lidocaine, lysine, meglumine,N-methyl-D-glucamine, morpholine, piperazine, piperidine, polyamineresins, procaine, purines, theobromine, triethanolamine, triethylamine,trimethylamine, tripropylamine and tris(hydroxy-methyl)methylamine(tromethamine), but this is not intended to represent a restriction.

Compounds of the present invention which contain basicnitrogen-containing groups can be quaternised using agents such as(C₁-C₄)alkyl halides, for example methyl, ethyl, isopropyl andtert-butyl chloride, bromide and iodide; di(C₁-C₄)alkyl sulfates, forexample dimethyl, diethyl and diamyl sulfate; (C₁₀-C₁₈)alkyl halides,for example decyl, dodecyl, lauryl, myristyl and stearyl chloride,bromide and iodide; and aryl(C₁-C₄)alkyl halides, for example benzylchloride and phenethyl bromide. Both water- and oil-soluble compoundsaccording to the invention can be prepared using such salts.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tromethamine, but this is not intended to represent arestriction.

Particular preference is given to hydrochloride, dihydrochloride,hydrobromide, maleate, mesylate, phosphate, sulfate and succinate.

The acid-addition salts of basic compounds of the formula I are preparedby bringing the free base form into contact with a sufficient amount ofthe desired acid, causing the formation of the salt in a conventionalmanner. The free base can be regenerated by bringing the salt form intocontact with a base and isolating the free base in a conventionalmanner. The free base forms differ in a certain respect from thecorresponding salt forms thereof with respect to certain physicalproperties, such as solubility in polar solvents; for the purposes ofthe invention, however, the salts otherwise correspond to the respectivefree base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanolamine, ethylenediamine, N-methyl-D-glucamine and procaine.

The base-addition salts of acidic compounds according to the inventionare prepared by bringing the free acid form into contact with asufficient amount of the desired base, causing the formation of the saltin a conventional manner. The free acid can be regenerated by bringingthe salt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts otherwise correspond tothe respective free acid forms thereof.

If a compound according to the invention contains more than one groupwhich is capable of forming pharmaceutically acceptable salts of thistype, the invention also encompasses multiple salts. Typical multiplesalt forms include, for example, bitartrate, diacetate, difumarate,dimeglumine, diphosphate, disodium and trihydrochloride, but this is notintended to represent a restriction.

With regard to that stated above, it can be seen that the expression“pharmaceutically acceptable salt” in the present connection is taken tomean an active ingredient which comprises a compound of the formula I inthe form of one of its salts, in particular if this salt form impartsimproved pharmacokinetic properties on the active ingredient comparedwith the free form of the active ingredient or any other salt form ofthe active ingredient used earlier. The pharmaceutically acceptable saltform of the active ingredient can also provide this active ingredientfor the first time with a desired pharmacokinetic property which it didnot have earlier and can even have a positive influence on thepharmacodynamics of this active ingredient with respect to itstherapeutic efficacy in the body.

Isotopes

There is furthermore intended that a compound of the formula I includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the formula I is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the formula I by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the formula I, aprodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labelled compound of the formula I can be used in a number ofbeneficial ways. For example, an isotope-labelled compound of theformula I into which, for example, a radioisotope, such as ³H or ¹⁴C,has been incorporated is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Inco-poration of heavier isotopes, forexample deuterium (²H), into a compound of the formula I has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodiment of thepresent invention. An isotope-labelled compound of the formula I canusually be prepared by carrying out the procedures disclosed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the formula Ifor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus causes a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the formula I that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula I with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula I are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theformula I which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improvement inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the formula I can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzene-sulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3. A method for the resolution of racemates containing estergroups (for example acetyl esters) is the use of enzymes, in particularesterases.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising at least one compound of the formula I and/orpharmaceutically acceptable salts, solvates, tautomers and stereoisomersthereof, including mixtures thereof in all ratios, and optionallyexcipients and/or adjuvants

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients, such as oneor more additional compounds of the present invention, or a prodrugcompound or other p70S6K inhibitors.

The pharmaceutical compositions include compositions suitable for oral,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In one embodiment, said compounds and pharmaceutical composition are forthe treatment of cancer such as brain, lung, colon, epidermoid, squamouscell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney,liver, ovarian, prostate, colorectal, uterine, rectal, oesophageal,testicular, gynecological, thyroid cancer, melanoma, hematologicmalignancies such as acute myelogenous leukemia, multiple myeloma,chronic myelogenous leukemia, myeloid cell leukemia, glioma, Kaposi'ssarcoma, or any other type of solid or liquid tumors. Preferably, thecancer to be treated is chosen from breast, colorectal, lung, prostateor pancreatic cancer or glioblastoma.

Exemplary disorders treated by the compounds of the invention includeprostate cancer, thyroid cancer, liver cancer, lung cancer, breastcancer, colon cancer, prostate cancer, pituitary tumors, carcinoma ofthe bladder, breast, colon (e.g. colorectal carcinomas such as colonadenocarcinoma and colon adenoma), kidney, epidermis, liver, lung, forexample adenocarcinoma, small cell lung cancer and non-small cell lungcarcinomas, esophagus, gall bladder, ovary, pancreas e.g. exocrinepancreatic carcinoma, stomach, cervix, endometrium, thyroid, prostate,or skin, for example squamous cell carcinoma; a hematopoietic tumour oflymphoid lineage, for example leukemia, acute lymphocytic leukemia,chronic lymphocytic leukemia, B-cell lymphoma, T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma; hairy cell lymphoma, orBurkett's lymphoma; a hematopoietic tumour of myeloid lineage, forexample leukemias, acute and chronic myelogenous leukemias,myeloproliferative syndrome, myelodysplastic syndrome, or promyelocyticleukemia; multiple myeloma; thyroid follicular cancer; a tumour ofmesenchymal origin, for example fibrosarcoma or rhabdomyosarcoma; atumour of the central or peripheral nervous system, for exampleastrocytoma, neuroblastoma, glioma or schwannoma; melanoma; seminoma;teratocarcinoma; osteosarcoma; xeroderma pigmentosum; keratoctanthoma;thyroid follicular cancer; or Kaposi's sarcoma.

In certain embodiments, the disorder is bladder cancer, breast cancer,cervical cancer, colon cancer, epidermis cancer, gall bladder cancer,kidney cancer, liver cancer, lung cancer, pituitary tumors, esophaguscancer, ovarian cancer, pancreatic cancer, prostate cancer, stomachcancer, thyroid cancer, leukemia, B-cell lymphoma, T-cell lymphoma,Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma,Burkett's lymphoma, acute and chronic myelogenous leukemias,myeloproliferative syndrome, myelodysplastic syndrome, promyelocyticleukemia; multiple myeloma, thyroid follicular cancer; astrocytoma,neuroblastoma, glioma, schwannoma, melanoma or Kaposi's sarcoma.

In certain embodiments, the disorder is multiple myeloma,myeloproliferative disorders, endometrial cancer, prostate cancer,bladder cancer, lung cancer, ovarian cancer, breast cancer, gastriccancer, colorectal cancer, and oral squamous cell carcinoma. In certainembodiments, the disorder is multiple myeloma, bladder cancer, cervicalcancer, prostate cancer, thyroid carcinomas, lung cancer, breast cancer,or colon cancer.

The invention also relates to the use of compounds according to theinvention for the preparation of a medicament for the treatment ofhyperproliferative diseases related to the hyperactivity of p70S6K aswell as diseases modulated by the p70S6K cascade in mammals, ordisorders mediated by aberrant proliferation, such as cancer andinflammation.

The invention also relates to a compound or pharmaceutical compositionfor treating a disease related to vasculogenesis or angiogenesis in amammal which comprises a therapeutically effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt, prodrugor hydrate thereof, and a pharmaceutically acceptable carrier.

In one embodiment, said compound or pharmaceutical composition is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,inflammatory bowel disease, atherosclerosis, skin diseases such aspsoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy,retinopathy of prematurity and age-related macular degeneration.

This invention also relates to a compound or pharmaceutical compositionfor inhibiting abnormal cell growth in a mammal which comprises anamount of a compound of the present invention, or a pharmaceuticallyacceptable salt or solvate or prodrug thereof, in combination with anamount of another anti-cancer therapeutic, wherein the amounts of thecompound, salt, solvate, or prodrug, and of the chemotherapeutic aretogether effective in inhibiting abnormal cell growth. Many anti-cancertherapeutics are presently known in the art. In one embodiment, theanti-cancer therapeutic is a chemotherapeutic selected from the groupconsisting of mitotic inhibitors, alkylating agents, anti-metabolites,intercalating antibiotics, growth factor inhibitors, cell cycleinhibitors, enzymes, topoisomerase inhibitors, biological responsemodifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.In another embodiment the anti-cancer therapeutic is an antibodyselected from the group consisting of bevacizumab, CD40-specificantibodies, chTNT-1/B, denosumab, zanolimumab, IGF1R-specificantibodies, lintuzumab, edrecolomab, WX G250, rituximab, ticilimumab,trastuzumab and cetuximab. In yet another embodiment the anti-cancertherapeutic is an inhibitor of another protein kinase, auch as Akt, Axl,Aurora A, Aurora B, dyrk2, epha2, fgfr3, igf1r, IKK2, JNK3, Vegfr1,Vegfr2, Vegfr3 (also known as Flt-4), KDR, MEK, MET, Plk1, RSK1, Src,TrkA, Zap70, cKit, bRaf, EGFR, Jak2, PI3K, NPM-Alk, c-Abl, BTK, FAK,PDGFR, TAK1, LimK, Flt-3, PDK1 and Erk.

The disclosed compounds of the formula I can be administered incombination with other known therapeutic agents, including anticanceragents. As used here, the term “anticancer agent” relates to any agentwhich is administered to a patient with cancer for the purposes oftreating the cancer.

The anti-cancer treatment defined above may be applied as a monotherapyor may involve, in addition to the herein disclosed compounds of formulaI, conventional surgery or radiotherapy or medicinal therapy. Suchmedicinal therapy, e.g. a chemotherapy or a targeted therapy, mayinclude one or more, but preferably one, of the following anti-tumoragents:

Alkylating agents: such as altretamine, bendamustine, busulfan,carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine,ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol,mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan,mechloretamine, carboquone; apaziquone, fotemustine, glufosfamide,palifosfamide, pipobroman, trofosfamide, uramustine, TH-302⁴, VAL-083⁴;Platinum Compounds: such as carboplatin, cisplatin, eptaplatin,miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin,satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;DNA altering agents: such as amrubicin, bisantrene, decitabine,mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine,brostallicin, pixantrone, laromustine^(1,3);Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane,sobuzoxane, teniposide, topotecan; amonafide, belotecan, elliptiniumacetate, voreloxin;Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin,ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine,vindesine, vinflunine; fosbretabulin, tesetaxel;Antimetabolites: such as asparaginase³, azacitidine, calciumlevofolinate, capecitabine, cladribine, cytarabine, enocitabine,floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine,methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine,thioguanine, carmofur; doxifluridine, elacytarabine, raltitrexed,sapacitabine, tegafur^(2,3), trimetrexate;Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin,epirubicin, idarubicin, levamisole, miltefosine, mitomycin C,romidepsin, streptozocin, valrubicin, zinostatin, zorubicin,daunurobicin, plicamycin; aclarubicin, peplomycin, pirarubicin;Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide,buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone,estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant,goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin,nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen,thyrotropin alfa, toremifene, trilostane, triptorelin,diethylstilbestrol; acolbifene, danazol, deslorelin, epitiostanol,orteronel, enzalutamide^(1,3);Aromatase inhibitors: such as aminoglutethimide, anastrozole,exemestane, fadrozole, letrozole, testolactone; formestane;Small molecule kinase inhibitors: such as crizotinib, dasatinib,erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib,ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib,gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib,dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib,linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib,perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib,tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib,apatinib⁴, cabozantinib S-malatel^(1,3), ibrutinib^(1,3), icotinib⁴,buparlisib², cipatinib⁴, cobimetinib^(1,3), idelalisib^(1,3),fedratinibl, XL-647⁴;Photosensitizers: such as methoxsalen³; porfimer sodium, talaporfin,temoporfin;Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin,cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab,tositumomab, trastuzumab, bevacizumab, pertuzumab^(2,3); catumaxomab,elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab,nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab,rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab,matuzumab, dalotuzumab^(1,2,3), onartuzumab^(1,3), racotumomab¹,tabalumab^(1,3), EMD-525797⁴, nivolumab^(1,3);Cytokines: such as aldesleukin, interferon alfa², interferon alfa2a³,interferon alfa2b^(2,3); celmoleukin, tasonermin, teceleukin,oprelvekin^(1,3), recombinant interferon beta-1a⁴;Drug Conjugates: such as denileukin diftitox, ibritumomab tiuxetan,iobenguane I123, prednimustine, trastuzumab emtansine, estramustine,gemtuzumab, ozogamicin, aflibercept;cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomabestafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab^(1,3),vintafolide^(1,3);Vaccines: such as sipuleucel³; vitespen³, emepepimut-S³, oncoVAX⁴,rindopepimut³, troVax⁴, MGN-1601⁴, MGN-1703⁴; andMiscellaneous: alitretinoin, bexarotene, bortezomib, everolimus,ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine,mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel³,sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin,vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide,entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib,lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin,pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat,thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar,gendicine⁴, picibanil⁴, reolysin⁴, retaspimycin hydrochloride^(1,3),trebananib^(2,3), virulizin⁴, carfilzomib^(1,3), endostatin⁴,immucothel⁴, belinostat³, MGN-1703⁴. (¹ Prop. INN (Proposedinternational Nonproprietary Name); ² Rec. INN (Recommendedinternational Nonproprietary Names); ³ USAN (United States AdoptedName); ⁴ no INN).

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal or treating a hyperproliferative disorder thatcomprises administering to the mammal an amount of a compound of thepresent invention, or a pharmaceutically acceptable salt or solvate orprodrug thereof, in combination with radiation therapy, wherein theamounts of the compound, salt, solvate, or prodrug, is in combinationwith the radiation therapy effective in inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of a compound of the invention in this combinationtherapy can be determined as described herein. It is believed that thecompounds of the present invention can render abnormal cells moresensitive to treatment with radiation for purposes of killing and/orinhibiting the growth of such cells.

Accordingly, this invention further relates to a method for sensitizingabnormal cells in a mammal to treatment with radiation which comprisesadministering to the mammal an amount of a compound of the presentinvention or pharmaceutically acceptable salt or solvate or prodrugthereof, which amount is effective is sensitizing abnormal cells totreatment with radiation. The amount of the compound, salt, or solvatein this method can be determined according to the means for ascertainingeffective amounts of such compounds described herein. The invention alsorelates to a method for inhibiting abnormal cell growth in a mammal thatcomprises an amount of a compound of the present invention, or apharmaceutically acceptable salt or solvate thereof, a prodrug thereof,or an isotopically-labeled derivative thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like. In the case of oral liquidpreparations, any of the usual pharmaceutical media may be employed,such as, for example, suspensions, elixirs and solutions; or carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. In the case of oral solid preparations the composition may takeforms such as, for example, powders, hard and soft capsules and tablets,with the solid oral preparations being preferred over the liquidpreparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating or preventing cancer, inflammation or other proliferativediseases for which compounds of the present invention are indicated,generally satisfactory results are obtained when the compounds of thepresent invention are administered at a daily dosage of from about 0.01milligram to about 100 milligram per kilogram of animal body weight,preferably given as a single daily dose. For most large mammals, thetotal daily dosage is from about 0.1 milligrams to about 1000milligrams, preferably from about 0.2 milligram to about 50 milligrams.In the case of a 70 kg adult human, the total daily dose will generallybe from about 0.2 milligrams to about 200 milligrams. This dosageregimen may be adjusted to provide the optimal therapeutic response.

The invention also relates to a set (kit) consisting of separate packsof

a) an effective amount of a compound according to the invention or/andpharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof, andb) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

Experimental Section

Some abbreviations that may appear in this application are as follows:

Abbreviations

Designation ACN acetonitrile AcOH Acetic acid AIBNAzobisisobutylonitrile ATP Adenosine triphosphate b Broad peak Bop-ClBis(2-oxo-3-oxazolidinyl)phosphinic chloride Conc. concentrated dDoublet DCM Dichloromethane DCE dichloroethane DMAPdimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxideDIEA/DIPEA N,N-Diisopropylethylamine DTT dithiothreitol EDTAEthylenediaminetetraacetic acid equiv./eq. equivalents Et ethyl h hourHEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HPLC Highpressure liquid chromatography LC/MS Liquid chromatography coupled tomass spectrometry LiOH Lithium hydroxide m multiplet M Molecular ion m/zMass-to-charge ratio Me methyl MeOH methanol min minute MS Massspectrometry N Normal (unit of concentration) NaOH Sodium hydroxide NBSN-bromosuccinimide NMO 4-methylmorpholine N-oxide NMPN-Methyl-2-pyrrolidone NMR Nuclear Magnetic Resonance PG Protectinggroup psi Pounds per square inch q Quartette (or quartet) Rf Retentionfactor RT/rt Room temperature Rt. Retention time s Singlet T3PPropylphosphonic anhydride TBAF Tetrabutylammonium fluoride TertTertiary TEA Triethylamine TFA Trifluoroacetic acid THABTetrahexylammonium bromide THF Tetrahydrofuran UV ultraviolet VISvisible

The compounds of the present invention can be prepared according to theprocedures of the following Schemes and Examples, using appropriatematerials and are further exemplified by the following specificexamples.

Moreover, by utilizing the procedures described herein, in conjunctionwith ordinary skills in the art, additional compounds of the presentinvention claimed herein can be readily prepared. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. The examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the art will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds.

The instant compounds are generally isolated in the form of theirpharmaceutically acceptable salts, such as those described above. Theamine-free bases corresponding to the isolated salts can be generated byneutralization with a suitable base, such as aqueous sodiumhydrogencarbonate, sodium carbonate, sodium hydroxide and potassiumhydroxide, and extraction of the liberated amine-free base into anorganic solvent, followed by evaporation. The amine-free base, isolatedin this manner, can be further converted into another pharmaceuticallyacceptable salt by dissolution in an organic solvent, followed byaddition of the appropriate acid and subsequent evaporation,precipitation or crystallization.

The invention will be illustrated, but not limited, by reference to thespecific embodiments described in the following schemes and examples.Unless otherwise indicated in the schemes, the variables have the samemeaning as described above. Unless otherwise specified, all startingmaterials are obtained from commercially suppliers and used withoutfurther purifications. Unless otherwise specified, all temperatures areexpressed in ° C. and all reactions are conducted at room temperature.Compounds were purified by either silica chromatography or preparativeHPLC.

The present invention also relates to processes for manufacturing thecompounds of Formula (I) according to the hereinafter described schemesand working examples.

Bicyclic scaffolds (1) are reacted with amines (2) under basic conditionto yield the compounds of Formula I (3). Unless otherwise designated thesubstituents in general synthetic scheme I correspond to those definedin Formula I.

In some embodiments, the bicyclic scaffold was prepared from4-amino-6-chloro-pyrimidin-5-ol reacting with 1,2-dibromo-ethane underbasic conditions.

In a preferred embodiment, a bicyclic scaffold (4) is reacted with amine(5) (WO13/40044) under basic conditions to yield compound (6) alsodescribed by Formula I. Unless otherwise designated the substituents ingeneral synthetic scheme II correspond to those defined in Formula I.

4,6-Dichloro-5-nitro-pyrimidine reacted with reagents (7) under basiccondition to provide chloride intermediates (8). Chlorides (8) reactedwith substituted amines to afford compounds (9). The bicyclic compounds(11) were obtained after de-boc of the ring closure product of compounds(10), which were yielded from the hydrogenation of compounds (9). Thealkylation of compounds (11) in the presence of base afforded thedesired compounds (12).

Analytical Methodology Analytical LC/MS was Performed Using theFollowing Three Methods: Method A:

A Discovery C¹⁸, 5 μm, 3×30 mm column was used at a flow rate of 400μL/min, sample loop 5 μL, mobile phase: (A) water with 0.1% formic acid,mobile phase, (B) methanol with 0.1% formic acid; retention times aregiven in minutes. Method details: (I) runs on a Quaternary Pump G1311A(Agilent) with UV/VIS diode array detector G1315B (Agilent) and FinniganLCQ Duo MS detector in ESI+modus with UV-detection at 254 and 280 nmwith a gradient of 15-95% (B) in a 3.2 min linear gradient (II) hold for1.4 min at 95% (B) (Ill) decrease from 95-15% (B) in a 0.1 min lineargradient (IV) hold for 2.3 min at 15% (B).

Method B:

A Waters Symmetry C¹⁸, 3.5 μm, 4.6×75 mm column at a flow rate of 1mL/min, sample loop 10 μL, mobile phase (A) is water with 0.05% TFA,mobile phase (B) is ACN with 0.05% TFA; retention times are given inminutes. Methods details: (I) runs on a Binary Pump G1312A (Agilent)with UV/Vis diode array detector G1315B (Agilent) and Agilent G1956B(SL) MS detector in ESI+mode with UV-detection at 254 and 280 nm with agradient of 20-85% (B) in a 10 min linear gradient (II) hold for 1 minat 85% (B) (Ill) decrease from 20-85% (B) in a 0.2 min linear gradient(IV) hold for 3.8 min at 20% (B).

Method C:

Gradient: 4.2 min/Flow: 2 ml/min 99:01-0:100 Water+0.1% (Vol.) TFA;Acetonitril+0.1% (Vol.) TFA; 0.0 to 0.2 min: 99:01; 0.2 to 3.8 min:99:01→0:100; 3.8 to 4.2 min: 0:100; Column: Chromolith PerformanceRP18e; 100 mm long, 3 mm diameter; Wavelength: 220 nm.

Analytical Chiral HPLC

Analytical chiral HPLC was performed using a ChiralPak AD-H column(250×4.6 mm) from Daicel Chemical Industries, Ltd. on an Agilent 1100Series system. The method used a 5.0 μL injection volume, with a flowrate of 1 mL/min of 100% methanol for 15 min at 25° C., and UV-detectionat 254 and 280 nm.

Preparative HPLC

Preparative HPLC was performed using either a Waters Atlantis dC₁₈ OBD™10 μM (30×250 mm) column or a Waters Sunfire Prep C₁₈ OBD 10 μM (30×250mm) column. The columns were used at a flow rate of 60 mL/min on aWaters Prep LC 4000 System equipped with a sample loop (10 mL) and anISCO UA-6 UV/Vis detector. The mobile phase was drawn from two solventreservoirs containing (A) water and (B) HPLC-grade acetonitrile. Atypical preparative run used a linear gradient (e.g., 0-60% solvent Bover 60 min).

EXAMPLES

The working examples presented below are intended to illustrateparticular embodiments of the invention, and are not intended to limitthe scope of the specification or the claims in any way.

Example 1 Compounds of Formula (I) according to General Synthetic SchemeII2-(1-(5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)piperidin-4-yl)-2-(4-trifluoromethyl)phenyl)ethanamine(“A1”)

Step 1: tert-butyl4-(2-(4-nitrophenylsulfonamido)-1-(4-(trifluoromethyl)phenyl)-ethyl)piperidine-1-carboxylate

To a solution of4-[2-amino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazine-1-carboxylicacid tert-butyl ester (1000.00 mg; 2.68 mmol; 1.00 eq.) anddiisopropylethylamine (0.58 ml; 3.21 mmol; 1.2 eq.) in 30 ml of DCM at0° C., 4-nitro-benzenesulfonyl chloride (593.50 mg; 2.68 mmol; 1.0 eq.)was added. The resulting mixture was stirred at rt for 2 hrs. Afterremoval of the solvent, the residue was subjected to snap column (elutedwith 0-50% ethyl acetate in hexane) to afford tert-butyl4-(2-(4-nitrophenylsulfonamido)-1-(4-(trifluoromethyl)phenyl)ethyl)piperidine-1-carboxylate(1050 mg, 70% yield).

Step 2:4-nitro-N-(2-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)-benzenesulfonamide

A reaction mixture of tert-butyl4-(2-(4-nitrophenylsulfonamido)-1-(4-(trifluoromethyl)phenyl)ethyl)piperidine-1-carboxylate(1050.0 mg; 1.88 mmol; 1.0 eq.) and 5 ml of 4M HCl in dioxane in 5 ml ofmethanol was stirred for 2 hr. After removal of the solvents, theresidue was treated with ether, collected the white solid HCl salt ofthe title compound (814 mg, 81.5% yield).

Step 3:4-nitro-N-(2-(1-(5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)benzenesulfonamide

A reaction mixture of 5-chloro-1,2,3,4-tetrahydro-[1,8]naphthyridine(50.0 mg; 0.3 mmol; 1.0 eq.),4-nitro-N-(2-(piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethyl)-benzenesulfonamide(157.56 mg; 0.30 mmol; 1.0 eq.) and diisopropylethylamine (0.27 ml; 1.5mmol; 5.0 eq.) in 1 ml of NMP was stirred at 140° C. for 36 hrs. Thecrude was purified by pre-HPLC to afford the title compound (100 mg);LC-MS (M+H=590, obsd.=591).

Step 4:2-(1-(5,6,7,8-tetrahydro-1,8-naphthyridin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine

A reaction mixture of4-nitro-N-[2-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethyl]-benzenesulfonamide(100.0 mg; 0.17 mmol; 1.0 eq.), benzenethiol (93.2 mg; 0.85 mmol; 5.0eq.), and cesium carbonate (551.6 mg; 1.69 mmol; 10.0 eq.) in 5 ml ofacetonitrile was stirred at 40° C. for 3 hrs. Little product was foundby lc-ms, added another 0.1 ml of benzenethiol and stirred overnight.The crude was purified by pre-HPLC to afford the title compound as whitesolid (9.7 mg); LC-MS (M+H=405, obsd.=406).

2-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine(“A2”)

Step 1:2-(1-(7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine

The reaction mixture of4-chloro-7-(4-methoxy-benzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine(60.0 mg; 0.22 mmol; 1.0 eq.),2-(piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanaminetrihydrochloride (83.27 mg; 0.22 mmol; 1.0 eq.) and potassium carbonate(0.42 ml; 2.18 mmol; 10.0 eq.) in 1.5 ml of DMF was stirred at 120° C.for 60 hrs. The crude was purified by pre-HPLC to afford the titlecompound (50 mg, 31% yield); LC-MS (M+H=511, obsd.=512).

Step 2:2-(1-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine

To2-(1-(7-(4-methoxybenzyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanaminebis(2,2,2-trifluoroacetate) (50.00 mg; 0.07 mmol; 1.00 eq.) in a sealedtube was added trifluoro-acetic acid (1.00 ml; 8.77 mmol; 129.91 eq.),and the reaction mixture was stirred at 80° C. overnight. The crude waspurified by pre-HPLC to afford the title product (5 mg, 11.9% yield);LC-MS (M+H=391, obsd.=392);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.19 (s, 1H), 6.82-6.84 (d, 2H),6.57-6.59 (d, 2H), 3.09-3.29 (m, 1H), 3.07-3.09 (m, 4H), 2.93-2.97 (m,3H), 2.93-2.99 (m, 3H), 1.87-1.91 (m, 2H), 1.24-1.59 (m, 2H).

2-(1-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-4-yl)-2-(4-(trifluoromethyl)phenyl)ethanamine(“A3”)

The reaction mixture of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidine(50.0 mg; 0.32 mmol; 1.0 eq.),2-(piperazin-1-yl)-2-(4-(trifluoromethyl)phenyl)ethanaminetrihydrochloride (148.52 mg; 0.39 mmol; 1.20 eq.) and potassiumcarbonate (268.19 mg; 1.94 mmol; 6.0 eq.) in 1.5 ml of DMF was stirredat 120° C. overnight. The crude was purified by pre-HPLC to afford thetitle product (50 mg, 21% yield); LC-MS (M+H=390, obsd.=391);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.63 (s, 1H), 7.94-8.01 (d, 3H),7.75-7.77 (d, 2H), 7.50-7.52 (d, 2H), 4.04-4.08 (m, 4H), 3.69-3.71 (m,1H), 3.03-3.07 (m, 3H), 2.90-2.91 (m, 2H), 2.63-2.64 (m, 2H), 2.31-2.33(m, 2H), 2.01-2.03 (m, 2H).

{2-(4-Chlorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine(“A4”)

Step 1: 4-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine

A reaction mixture of 4-amino-6-chloro-pyrimidin-5-ol (500.0 mg; 3.44mmol; 1.0 eq.), cesium carbonate (2238 mg; 6.87 mmol; 2.0 eq.), and1,2-dibromo-ethane (645.3 mg; 3.44 mmol; 1.0 eq.) in 10 ml of acetonewas stirred at 65° C. for 14 hours. To the reaction solution was added50 mL of ethyl acetate, washed with water, then brine and dried. Thesolvents were removed to give the residue, which was treated with ether,stirred for 30 min, filtered, to yield4-chloro-7,8-dihydro-6H-pryrimido[5,4-b][1,4]oxazine as yellow solid(227 mg, 38.5% yield). LC-MS (M+H=172, obsd.=172/174).

Step 2:{2-(4-Chlorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine

A mixture of [2-(4-Chloro-phenyl)-2-piperazin-1-yl-ethyl]-dimethyl-amine(300.0 mg; 1.03 mmol; 1.00 eq.),4-Chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (196.49 mg; 1.13mmol; 1.10 eq.) and potassium carbonate (363.37 mg; 2.58 mmol; 2.50 eq.)in DMSO (3.00 ml) was irradiated under microwave at 190° C. for 3 h. Thereaction mixture was cooled to RT, diluted with water (20 mL), andextracted with DCM (3×20 mL). The combined organic layer was washed withbrine solution, dried over Na₂SO₄ and concentrated under vacuum. Theresulted brown thick residue was purified by biotage using DCM/MeOH asan elutent to yield brown gum. The gummy solid was triturated withdiethylether (3 mL), filtered and dried under suction to afford thetitle compound as brown solid (36.00 mg, 8.2% yield). LC-MS (M+H=403,obsd.=403);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.63 (s, 1H), 7.37-7.35 (m, 2H),7.29-7.26 (m, 2H), 6.98 (bs, 1H), 3.99 (t, J=4.2 Hz, 2H), 3.67 (bs, 1H),3.44 (bs, 4H), 3.33 (bs, 2H), 2.75 (bs, 1H), 2.37 (bs, 4H), 2.10 (bs,6H).

[2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethyl]-dimethylamine(“A5”)

The title compound was prepared according to the procedure described forthe preparation of A4, using[2-(4-trifluoromethylphenyl)-2-piperazin-1-yl-ethyl]-dimethyl-amine asthe starting material. LC-MS (M+H=437, obsd.=437);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.67 (d, J=7.4 Hz, 2H), 7.63 (s, 1H),7.49 (d, J=8.1 Hz, 2H), 6.98 (bs, 1H), 3.99 (t, J=4.2 Hz, 2H), 3.76 (bs,1H), 3.43-3.42 (m, 4H), 3.32 (bs, 2H), 2.81 (bs, 1H), 2.59 (bs, 1H),2.39 (bs, 4H), 2.10 (bs, 6H).

[2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethyl]-dimethylamine(“A6”)

A mixture ofdimethyl-[2-piperazin-1-yl-2-(4-trifluoromethyl-phenyl)-ethyl]-amine(300.00 mg; 0.96 mmol; 1.00 eq.),4-Chloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (156.52 mg; 0.96 mmol;1.00 eq.) and potassium carbonate (336.95 mg; 2.39 mmol; 2.50 eq.) indry DMSO (3.00 ml) was irradiated at 190° C. for 3 h. The reactionmixture was cooled to RT, diluted with water (25 mL), and extracted withDCM (3×10 ml). The combined organic layer was washed with water, brinesolution, dried over Na₂SO₄ and concentrated under vacuum. The resultedbrown thick residue was purified by biotage using DCM/MeOH as an elutentto yield brown gum. This gum was further azeotroped with diethylether(2×10 ml) to obtain foamy solid. Then this solid was further treatedwith diethyl ether/hexane mixture (1:1, 5 ml). The solvent portion wassyringed out and the remaining solid was further dried under vacuum toafford the title compound as pale brown solid (34.00 mg, 8.2% yield).LC-MS (M+H=421, obsd.=421);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.80 (s, 1H), 7.67 (d, J=7.7 Hz, 2H),7.50 (d, J=8.1 Hz, 2H), 6.56 (bs, 1H), 3.76 (s, 1H), 3.50-3.48 (m, 4H),3.37 (bs, 2H), 3.01 (t, J=8.6 Hz, 2H), 2.79 (bs, 2H), 2.50-2.49 (m, 1H),2.39 (bs, 4H), 2.10 (bs, 6H).

{2-(4-Chlorophenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine(“A7”)

The title compound was prepared according to the procedure described forthe preparation of A6, using[2-(4-chlorophenyl)-2-piperazin-1-yl-ethyl]dimethyl-amine as thestarting material. LC-MS (M+H=387, obsd.=387);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.80 (s, 1H), 7.35 (d, J=8.4 Hz, 2H),7.28 (d, J=8.5 Hz, 2H), 6.56 (bs, 1H), 3.66-3.63 (m, 1H), 3.51-3.43 (m,4H), 3.37-3.36 (m, 2H), 3.01 (t, J=8.7 Hz, 2H), 2.73-2.66 (m, 1H),2.60-2.57 (m, 1H), 2.40-2.32 (m, 4H), 2.09 (s, 6H).

{2-(4-Chlorophenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine(“A8”)

A mixture of [2-(4-Chloro-phenyl)-2-piperazin-1-yl-ethyl]-dimethyl-amine(300.00 mg; 1.03 mmol; 1.00 eq.),4-Chloro-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine (184.01 mg; 1.03mmol; 1.00 eq.) and potassium carbonate (363.37 mg; 2.58 mmol; 2.50 eq.)in dry DMSO (3.00 ml; 10.00 V) was irradiated at 190° C. for 3 h. Thereaction mixture was cooled to RT, diluted with water (25 mL), andextracted with DCM (3×10 ml). The combined organic layer was washed withwater, brine solution, dried over Na₂SO₄ and concentrated under vacuum.The resulted residue was purified by biotage using DCM/MeOH as anelutent to yield brown gum. This gum was further azeotroped withdiethylether (2×10 ml) to obtain foamy solid. Then this solid wasfurther treated with diethyl ether/hexane mixture (1:1, 5 ml), filteredand dried under suction to afford the title compound as pale brown solid(66.00 mg, 15.6% yield). LC-MS (M+H=401, obsd.=401);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.87 (s, 1H), 7.37 (d, J=8.2 Hz, 2H),7.29 (d, J=8.5 Hz, 2H), 6.86 (bs, 1H), 3.68 (bs, 1H), 3.17-3.15 (m, 2H),3.10 (bs, 4H), 2.76 (bs, 1H), 2.37 (bs, 4H), 2.36-2.32 (m, 2H), 2.11(bs, 6H), 1.62-1.59 (m, 2H).

Dimethyl-[2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethyl]-amine(“A9”)

The title compound was prepared according to the procedure described forthe preparation of A8, using[2-(4-trifluoromethylphenyl)-2-piperazin-1-yl-ethyl]-dimethyl-amine asthe starting material. LC-MS (M+H=435, obsd.=435);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.87 (s, 1H), 7.68 (d, J=8.1 Hz, 2H),7.51 (d, J=8.0 Hz, 2H), 6.87 (s, 1H), 3.79-3.75 (m, 1H), 3.16-3.15 (m,2H), 3.10 (bs, 4H), 2.84-2.78 (m, 1H), 2.50-2.49 (m, 1H), 2.37-2.34 (m,6H), 2.11 (s, 6H), 1.60 (bs, 2H).

2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethylphenyl)-ethylamine(“A10”)

A mixture of 2-piperazin-1-yl-2-(4-trifluoromethylphenyl)-ethylaminedihydrochloride (500 mg; 1.1 mmol; 1.0 eq.),4-chloro-7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazine (200 mg; 1.1 mmol;1.0 eq.) and potassium carbonate (804 mg; 5.7 mmol; 5.0 eq.) in dry DMSO(5.0 ml) was heated to 100° C. for 3 days. The reaction mixture wascooled to RT, diluted with water (100 mL) and extracted with DCM (2×100mL). The combined organic layer was washed further with water (50 mL),brine solution, dried over Na₂SO₄ and concentrated under vacuum. Theresulted residue was purified by Biotage eluting with DCM in MeOH; theresultant product was further purified by Prep. HPLC to afford the titlecompound as yellow solid (14.0 mg; 2.9% yield). LC-MS (M+H=409,obsd.=409);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.69 (d, J=8.1 Hz, 2H), 7.64 (s, 1H),7.47 (d, J=8.0 Hz, 2H), 7.00 (s, 1H), 3.99 (t, J=4.2 Hz, 2H), 3.98-3.43(m, 7H), 3.07-3.02 (m, 1H), 2.84-2.79 (m, 1H), 2.37-2.32 (m, 4H), 1.55(br s, 1H).

2-(4-Chlorophenyl)-2-[4-(7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-ethylamine(“A11”)

The title compound was prepared according to the procedure described forthe preparation of A10, using2-(4-chlorophenyl)-2-piperazin-1-yl-ethylamine dihydrochloride as thestarting material. LC-MS (M+H=375, obsd.=375);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.63 (s, 1H), 7.38 (d, J=8.4 Hz, 2H),7.26 (d, J=8.4 Hz, 2H), 6.99 (br s, 1H), 3.99 (t, J=4.3 Hz, 2H),3.49-3.48 (m, 1H), 3.47-3.45 (m, 4H), 3.40-3.38 (m, 2H), 3.06-3.01 (m,1H), 2.77-2.72 (m, 1H), 2.39-2.30 (m, 5H).

[2-[4-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperazin-1-yl]-2-(3-fluoro-4-trifluoromethylphenyl)-ethyl]-dimethylamine(“A12”)

The title compound was prepared according to the procedure described forthe preparation of A4, using[2-(3-fluoro-4-trifluoromethyl-phenyl)-2-piperazin-1-yl-ethyl]-dimethylamineas the starting material. LC-MS (M+H=455, obsd.=455);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.77 (d, J=6.2 Hz, 1H), 7.74 (s, 1H),7.46 (d, J=12.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.00 (s, 1H), 3.99 (t,J=4.2 Hz, 3H), 3.47 (s, 4H), 3.00 (br s, 2H), 2.45-2.44 (m, 4H), 2.37(br s, 6H).

2-(4-Chloro-phenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine(“A13”)

The title compound was prepared according to the procedure described forthe preparation of A10, using2-(4-chlorophenyl)-2-piperazin-1-yl-ethylamine dihydrochloride and4-chloro-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine as the startingmaterials. LC-MS (M+H=359, obsd.=359);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.80 (s, 1H), 7.38 (d, J=8.4 Hz, 2H),7.26 (d, J=8.4 Hz, 2H), 6.57 (br s, 1H), 3.51-3.49 (m, 5H), 3.49-3.48(m, 1H), 3.04-2.99 (m, 3H), 2.78-2.73 (m, 1H), 2.37-2.32 (m, 5H), 1.69(br s, 2H).

2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-fluorophenyl)-ethylamine(“A14”)

The title compound was prepared according to the procedure described forthe preparation of A13, using2-(4-fluorophenyl)-2-piperazin-1-yl-ethylamine dihydrochloride as thestarting material. LC-MS (M+H=343, obsd.=343);

{2-(4-Chloro-3-fluoro-phenyl)-2-[4-(6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine(“A15”)

The title compound was prepared according to the procedure described forthe preparation of A13, using[2-(4-chloro-3-fluoro-phenyl)-2-piperazin-1-yl-ethyl]-dimethyl-amine asthe starting material. LC-MS (M+H=405, obsd.=405);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.80 (s, 1H), 7.51 (t, J=8.00 Hz,1H), 7.34 (dd, J=1.72, 10.68 Hz, 1H), 7.14 (dd, J=1.68, 8.26 Hz, 1H),6.57 (s, 1H), 3.73 (s, 1H), 3.48 (dd, J=4.16, Hz, 4H), 3.39-3.40 (m,2H), 3.02 (t, J=8.88 Hz, 2H), 2.74-2.78 (m, 1H), 2.50-2.55 (m, 1H), 2.37(s, 4H), 2.11 (s, 6H).

2-[4-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(4-trifluoromethyl-phenyl)-ethylamine(“A16”)

The title compound was prepared according to the procedure described forthe preparation of A10, using4-chloro-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidine as the startingmaterial. LC-MS (M+H=407, obsd.=407);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.88 (s, 1H), 7.70 (d, J=8.1 Hz, 2H),7.49 (d, J=7.9 Hz, 2H), 6.88 (s, 1H), 3.48 (t, J=6.5 Hz, 2H), 3.17-3.13(m, 6H), 3.13-3.03 (m, 1H), 2.84-2.79 (m, 2H), 2.41-2.32 (m, 5H),1.62-1.61 (m, 3H).

2-(4-Chloro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine(“A17”)

The title compound was prepared according to the procedure described forthe preparation of A16, using2-(4-chlorophenyl)-2-piperazin-1-yl-ethylamine dihydrochloride as thestarting material. LC-MS (M+H=373, obsd.=373);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.87 (s, 1H), 7.39 (d, J=8.4 Hz, 2H),7.27 (d, J=8.4 Hz, 2H), 6.87 (br s, 1H), 3.40-3.37 (m, 1H), 3.17-3.15(m, 2H), 3.15-3.12 (m, 4H), 3.05-3.00 (m, 1H), 2.41-2.35 (m, 6H),1.62-1.59 (m, 4H).

{2-(4-Chloro-3-fluoro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine(“A18”)

The title compound was prepared according to the procedure described forthe preparation of A16, using[2-(4-chloro-3-fluoro-phenyl)-2-piperazin-1-yl-ethyl]-dimethylamine asthe starting material. LC-MS (M+H=419, obsd.=419);

{2-(3-Fluoro-4-trifluoromethyl-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-dimethylamine(“A19”)

The title compound was prepared according to the procedure described forthe preparation of A16, using[2-(3-fluoro-4-trifluoromethyl-phenyl)-2-piperazin-1-yl-ethyl]-dimethylamineas the starting material. LC-MS (M+H=453, obsd.=453);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.87 (s, 1H), 7.73 (t, J=7.8 Hz, 1H),7.46 (d, J=12.1 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 6.87 (s, 1H), 3.82 (s,1H), 3.17-3.11 (m, 6H), 2.86 (t, J=9.8 Hz, 1H), 2.38-2.35 (m, 6H), 2.11(s, 6H), 1.61 (t, J=4.68 Hz, 2H).

[2-[4-(6,7-Dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-dimethylamine(“A20”)

The title compound was prepared according to the procedure described forthe preparation of A6, using[2-(3-fluoro-4-trifluoromethyl-phenyl)-2-piperazin-1-yl-ethyl]-dimethyl-amineas the starting material. LC-MS (M+H=439, obsd.=439);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.80 (s, 1H), 7.71 (t, J=7.9 Hz, 1H),7.45 (d, J=12.0 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 6.58 (s, 1H), 3.82-3.79(m, 1H), 3.49 (t, J=3.8 Hz, 4H), 3.37-3.33 (m, 2H), 3.04-3.00 (m, 2H),2.86-2.81 (m, 1H), 2.50-2.48 (m, 1H), 2.40-2.38 (m, 4H), 2.10 (s, 6H).

2-(4-Fluoro-phenyl)-2-[4-(5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-ethylamine(“A21”)

The title compound was prepared according to the procedure described forthe preparation of A16, using2-(4-fluorophenyl)-2-piperazin-1-yl-ethylamine dihydrochloride as thestarting material. LC-MS (M+H=357, obsd.=357);

2-[1-(5,6,7,8-Tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperidin-4-yl]-2-(4-trifluoromethyl-phenyl)-ethylamine(“A22”)

The title compound was prepared according to the procedure described forthe preparation of A16, using2-piperidin-4-yl-2-(4-trifluoromethyl-phenyl)-ethylaminetrihydrochloride as the starting material. LC-MS (M+H=406, obsd.=406);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.99 (s, 1H), 7.66 (s, 2H), 7.42-7.40(d, J=8.0 Hz, 2H), 6.82 (s, 1H), 3.65-3.61 (d, J=12.6 Hz, 1H), 3.51-3.33(m, 1H), 3.18 (s, 2H), 2.99-2.84 (m, 1H), 2.82-2.50 (m, 1H), 2.40-2.37(m, 4H), 1.89-1.86 (d, J=12.28 Hz, 2H), 1.79-1.77 (d, J=8.48 Hz, 2H),1.63-1.61 (d, J=10.48 Hz, 2H), 1.33-1.22 (m, 3H), 1.05-1.02 (m, 1H).

2-[1-(7,8-Dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-yl)-piperidin-4-yl]-2-(4-trifluoromethyl-phenyl)-ethylamine(“A23”)

The title compound was prepared according to the procedure described forthe preparation of A10, using2-piperidin-4-yl-2-(4-trifluoromethyl-phenyl)-ethylaminetrihydrochloride as the starting material. LC-MS (M+H=408, obsd.=408);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.66-7.63 (m, 1H), 7.41-7.39 (d,J=8.1 Hz, 2H), 6.9 (s, 1H), 4.29-4.27 (d, 1H), 4.17-4.14 (d, 1H),4.00-3.98 (m, 2H), 2.98-2.88 (m, 1H), 2.85-2.82 (m, 1H), 2.71-2.66 (m,3H), 1.88-1.81 (m, 2H), 1.23-1.23 (m, 3H), 1.01-0.93 (m, 1H), 0.87-0.85(m, 1H).

Example Compounds of Formula (I) According to General Synthetic SchemeIII4-{4-[2-dimethylamino-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A24”)

Step 1: (6-chloro-5-nitro-pyrimidin-4-ylamino)-acetic acid ethyl ester

To amino-acetic acid ethyl ester hydrochloride (1439.15 mg; 10.31 mmol;1.00 eq.) and 4,6-Dichloro-5-nitro-pyrimidine (2000.00 mg; 10.31 mmol;1.00 eq.) in dry DMF (26 mL) was added ethyl-diisopropyl-amine (3997.72mg; 30.93 mmol; 3.00 eq.) and the mixture was stirred for 3 hours. LC-MSshowed that the reaction was complete. The DMF was removed and the EtOAcwas added. The mixture was washed with brine, dried over MgSO4 andpurified through flash chromatography on silica (EtOAc in Hexane from 0%to 30%) to provide (6-chloro-5-nitro-pyrimidin-4-ylamino)-acetic acidethyl ester 2.1 g with 78% yield; LC/MS: 261 (M+H)

Step 2:4-[6-(ethoxycarbonylmethyl-amino)-5-nitro-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester

The mixture of piperazine-1-carboxylic acid tert-butyl ester (800.00 mg;4.30 mmol; 1.00 eq.), (6-chloro-5-nitro-pyrimidin-4-ylamino)-acetic acidethyl ester (1119.49 mg; 4.30 mmol; 1.00 eq.) and potassium carbonate(1.78 g; 12.89 mmol; 3.00 eq.) in anhydrous DMF (5 mL) was stirred at60° C. for 5 hours. LC/MS showed the reaction was complete. Afterpouring to the water, the solid was precipitated, filtered and dried,1.4 g in 79% yield; LC-MS (M+1: 411, obsd: 411).

Step 3:4-[5-amino-6-(ethoxycarbonylmethyl-amino)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester

The mixture of4-[6-(ethoxycarbonylmethyl-amino)-5-nitro-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (1400.00 mg; 3.41 mmol; 1.00 eq.) and Pd/C (300mg) in MeOH (30 mL) was hydrogenated under 20 psi for 2 hours. Afterfiltration, the solvent was removed and the crude was used for the nextreaction (1.0 g, 77% yield); LC-MS (M+1: 381, obsd: 381).

Step 4: 4-piperazin-1-yl-7,8-dihydro-5H-pteridin-6-one hydrochloride

The solution of4-[5-amino-6-(ethoxycarbonylmethyl-amino)-pyrimidin-4-yl]-piperazine-1-carboxylicacid tert-butyl ester (700.00 mg; 1.84 mmol; 1.00 eq.) in EtOH (20 mL)was refluxed for 15 hours. After concentration, the crude product wasobtained and used for the next reaction.

The above crude product was suspended in 10 mL HCl in dioxane (4.0 M)and stirred for 1 h. LC/MS showed that the reaction was complete. Afterremoval of the solvent, ether was added and the solid was filtered anddried; 400 mg in 80% in yield; LC-MS (M+1: 235, obsd: 235).

Step 5:4-{4-[2-dimethylamino-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one

A mixture of [2-chloro-2-(4-fluoro-phenyl)-ethyl]-dimethyl-aminehydrochloride (50.00 mg; 0.21 mmol; 1.00 eq.),4-piperazin-1-yl-7,8-dihydro-5H-pteridin-6-one hydrochloride (56.84 mg;0.21 mmol; 1.00 eq.) and ethyl-diisopropyl-amine (0.19 ml; 1.05 mmol;5.00 eq.) in CAN (5 mL) in the sealed vial was stirred at 70° C. forovernight. The product was purified through reverse phase HPLC. 18 mg in21% yield; LC-MS (M+1: 400, obsd: 400);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 2.26 (6H), 2.63 (1H), 2.84 (1H), 2.88(1H), 3.95 (2H), 4.14 (1H), 7.19 (2H), 7.27 (2H), 8.14 (1H).

4-{4-[2-dimethylamino-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A25”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(3-fluoro-phenyl)-ethyl]-dimethyl-amine hydrochloride as thestarting material. LC-MS: (M+1=400, obsd.=400);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 2.27 (6H), 2.65 (1H), 2.86 (1H), 2.87(1H), 3.98 (2H), 4.16 (1H), 6.83 (1H), 7.06 (2H), 7.38 (1H), 8.14 (1H).

4-{4-[2-dimethylamino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A26”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-chloro-phenyl)-ethyl]-dimethyl-amine hydrochloride as thestarting material. LC-MS: (M+1=400, obsd.=400);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 2.24 (6H), 2.61 (1H), 2.82 (1H), 2.89(1H), 3.95 (2H), 4.14 (1H), 7.44 (2H), 7.48 (2H), 8.14 (1H).

4-{4-[2-dimethylamino-1-(3-chloro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A27”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(3-chloro-phenyl)-ethyl]-dimethyl-amine hydrochloride as thestarting material. LC-MS: (M+1=400, obsd.=400);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 2.27 (6H), 2.65 (1H), 2.86 (1H), 2.87(1H), 3.98 (2H), 4.16 (1H), 7.17 (1H), 7.31-7.34 (2H), 7.49 (1H), 8.14(1H).

4-{4-[2-dimethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A28”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-trifluoromethyl-phenyl)-ethyl]-dimethyl-aminehydrochloride as the starting material. LC-MS: (M+1=450, obsd.=450);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 2.26 (6H), 2.63 (1H), 2.84 (1H), 2.88(1H), 3.95 (2H), 4.14 (1H), 7.22 (2H), 7.57 (2H), 8.14 (1H).

4-{4-[1-(4-fluoro-phenyl)-2-(pyrrolidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A29”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-fluoro-phenyl)-ethyl]-pyrrolidine hydrochloride as thestarting material. LC-MS: (M+1=426, obsd.=426);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.68 (4H), 2.26 (4H), 2.63 (1H), 2.86(1H), 2.89 (1H), 3.98 (2H), 4.16 (1H), 7.19 (2H), 7.28 (2H), 8.14 (1H).

4-{4-[1-(4-chloro-phenyl)-2-(pyrrolidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A30”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-chloro-phenyl)-ethyl]-pyrrolidine hydrochloride as thestarting material. LC-MS: (M+1=442, obsd.=442);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.67 (4H), 2.26 (4H), 2.65 (1H), 2.80(1H), 2.84 (1H), 3.98 (2H), 4.17 (1H), 7.44 (2H), 7.48 (2H), 8.14 (1H).

4-{4-[1-(4-fluoro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A31”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-fluoro-phenyl)-ethyl]-piperidine hydrochloride as thestarting material. LC-MS: (M+1=440, obsd.=440);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.53 (4H), 1.59 (2H), 2.46 (4H), 2.63(1H), 2.86 (1H), 2.89 (1H), 3.98 (2H), 4.16 (1H), 7.19 (2H), 7.28 (2H),8.14 (1H).

4-{4-[1-(4-chloro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A32”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-chloro-phenyl)-ethyl]-piperidine hydrochloride as thestarting material. LC-MS: (M+1=457, obsd.=457);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.52 (4H), 1.60 (2H), 2.47 (4H), 2.62(1H), 2.86 (1H), 2.89 (1H), 3.98 (2H), 4.16 (1H), 7.44 (2H), 7.48 (2H),8.14 (1H).

4-{4-[1-(4-trifluoro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A33”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-trifluoro-phenyl)-ethyl]-piperidine hydrochloride as thestarting material. LC-MS: (M+1=490, obsd.=490);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.50 (4H), 1.57 (2H), 2.43 (4H), 2.65(1H), 2.85 (1H), 2.90 (1H), 3.98 (2H), 4.16 (1H), 7.26 (2H), 7.59 (2H),8.14 (1H).

4-{4-[2-Pyrrolidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A34”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-trifluoromethyl-phenyl)-ethyl]-pyrrolidine hydrochlorideas the starting material. LC-MS: (M+1=476, obsd.=476);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 1.68 (4H), 2.28 (4H), 2.66 (1H), 2.81(1H), 2.86 (1H), 3.98 (2H), 4.17 (1H), 7.29 (2H), 7.63 (2H), 8.14 (1H).

4-(4-(1-(2-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A35”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(2-chlorophenyl)-ethyl]-pyrrolidine hydrochloride as thestarting material. LC-MS: (M+1=426, obsd.=426);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.72 (s, 1H), 7.38 (d, J=7.4 Hz, 1H),7.28 (d, J=20.9 Hz, 1H), 7.14 (t, J=6.5 Hz, 1H), 7.05 (t, J=10.8 Hz,1H), 3.94 (s, 3H), 3.13-3.02 (m, 5H), 2.89-2.85 (m, 1H), 2.56-2.54 (m,4H), 2.40-2.37 (m, 4H), 2.29-2.28 (m, 4H).

4-(4-(2-(dimethylamino)-1-(2-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A36”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(2-fluorophenyl)-N,N-dimethylethanamine hydrochloride as thestarting material. LC-MS: (M+1=400, obsd.=400);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.63 (s, 1H), 7.81 (s, 1H), 7.36 (t,J=7.0 Hz, 2H), 7.28 (s, 1H), 7.23 (d, J=7.1 Hz, 2H), 3.79 (s, 5H), 3.33(s, 1H), 3.19 (s, 6H), 2.66 (s, 1H), 2.59 (s, 2H), 2.49 (t, J=1.60 Hz,2H), 2.32 (s, 2H).

4-(4-(2-(azetidin-1-yl)-1-(2-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A37”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(2-fluorophenyl)-ethyl)-azetidine hydrochloride as thestarting material. LC-MS: (M+1=412, obsd.=412);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.57 (s, 1H), 7.83 (s, 1H), 7.44-7.40(m, 1H), 7.26 (dd, J=11.5, 16.2 Hz, 2H), 7.17-7.09 (m, 2H), 3.79 (t,J=1.2 Hz, 3H), 3.12-3.02 (m, 8H), 2.50-2.48 (m, 5H), 2.35-2.31 (m, 1H),1.90 (t, J=6.8 Hz, 2H)

4-(4-(1-(2-fluorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A38”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(2-fluorophenyl)-ethyl)-piperidine hydrochloride as thestarting material. LC-MS: (M+1=440, obsd.=440);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.61 (s, 1H), 7.81 (s, 1H), 7.37 (t,J=6.7 Hz, 1H), 7.28 (d, J=8.1 Hz, 2H), 7.15 (dd, J=7.1, 17.1 Hz, 2H),4.04 (t, J=7.0 Hz, 1H), 3.78 (s, 2H), 3.16 (s, 4H), 2.66 (s, 3H), 2.49(s, 3H), 2.30 (t, J=10.68 Hz, 2H), 1.31 (s, 8H).

4-(4-(2-amino-1-(2-chlorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A39”)

The title compound was prepared according to the procedure described forthe preparation of A24, using 2-chloro-2-(2-chlorophenyl)-ethanaminehydrochloride as the starting material. LC-MS: (M+1=388, obsd.=388);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.62 (s, 1H), 7.86 (s, 1H), 7.75 (dd,J=1.5, 7.7 Hz, 1H), 7.38-7.30 (m, 3H), 7.26-7.22 (m, 1H), 4.50 (dd,J=3.5, 9.5 Hz, 1H), 3.82 (s, 2H), 3.25 (s, 5H), 2.69-2.66 (m, 1H),2.50-2.48 (m, 1H), 2.32 (d, J=3.60 Hz, 1H), 2.25 (t, J=9.80 Hz, 2H).

4-(4-(1-(2-chlorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A40”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(2-chlorophenyl)-N,N-dimethylethanamine hydrochloride as thestarting material. LC-MS: (M+1=416, obsd.=416);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.62 (s, 1H), 7.82 (s, 1H), 7.46 (d,J=0.0 Hz, 2H), 7.35 (s, 1H), 7.31 (t, J=7.4 Hz, 2H), 4.22 (s, 1H), 3.79(s, 2H), 3.15 (s, 4H), 2.59 (s, 2H), 2.49 (s, 4H), 2.12 (s, 6H).

4-(4-(1-(2-chlorophenyl)-2-(methylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A41”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(2-chlorophenyl)-N-methylethanamine hydrochloride as thestarting material. LC-MS: (M+1=402, obsd.=402);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.63 (s, 1H), 8.17 (s, 1H), 7.86 (s,1H), 7.66 (s, 1H), 7.64 (t, J=6.2 Hz, 1H), 7.42-7.31 (m, 1H), 7.29-7.25(m, 2H), 4.20 (dd, J=4.4, 9.0 Hz, 1H), 3.82 (s, 2H), 3.29-3.24 (m, 4H),3.19 (d, J=0.00 Hz, 2H), 2.50-2.49 (m, 2H), 2.38-2.31 (m, 2H), 2.19 (s,3H).

4-(4-(2-(azetidin-1-yl)-1-(2-chlorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A42”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(2-chlorophenyl)-ethyl)-azetidine hydrochloride as thestarting material. LC-MS: (M+1=428, obsd.=428);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.77 (s, 1H), 7.93 (s, 1H), 7.66-7.59(m, 2H), 7.49-7.45 (m, 3H), 5.15 (d, J=5.6 Hz, 1H), 4.18 (d, J=8.1 Hz,2H), 4.04 (t, J=7.7 Hz, 2H), 3.87 (s, 2H), 3.28 (s, 4H), 2.89 (s, 1H),2.77 (s, 2H), 2.50-2.48 (m, 3H), 2.36-2.30 (m, 2H).

4-(4-(1-(2-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A43”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(2-chlorophenyl)-ethyl)-pyrrolidine hydrochloride as thestarting material. LC-MS: (M+1=442, obsd.=442);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.62 (s, 1H), 7.82 (s, 1H), 7.47-7.41(m, 2H), 7.33 (t, J=6.4 Hz, 1H), 7.26 (t, J=7.6 Hz, 2H), 4.21 (d, J=7.0Hz, 1H), 3.79 (s, 2H), 3.15 (s, 4H), 2.93 (t, J=12.0 Hz, 1H), 2.79 (s,1H), 2.66-2.60 (m, 2H), 2.50-2.49 (m, 8H), 1.59 (s, 4H).

4-(4-(1-(2-chlorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A44”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(2-chlorophenyl)-ethyl)-piperidine hydrochloride as thestarting material. LC-MS: (M+1=456, obsd.=456);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.62 (s, 1H), 7.82 (s, 1H), 7.47-7.40(m, 1H), 7.32 (t, J=7.0 Hz, 1H), 7.27 (d, J=11.9 Hz, 3H), 4.18 (s, 1H),3.79 (s, 2H), 3.15 (s, 4H), 2.71 (s, 1H), 2.67-2.61 (m, 4H), 2.32 (t,J=1.80 Hz, 4H), 1.43-0.00 (m, 7H).

4-(4-(2-(dimethylamino)-1-(o-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A45”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-N,N-dimethyl-2-(o-tolyl)-ethanamine hydrochloride as thestarting material. LC-MS: (M+1=396, obsd.=396);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.58 (s, 1H), 7.82 (s, 1H), 7.28 (s,2H), 7.15 (s, 3H), 3.80 (d, J=1.2 Hz, 4H), 3.15 (s, 5H), 2.66 (t, J=1.8Hz, 4H), 2.36 (s, 3H), 2.12 (s, 6H).

4-(4-(2-(pyrrolidin-1-yl)-1-(o-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A46”)

The title compound was prepared according to the procedure described forthe preparation of A24, using 1-(2-chloro-2-(o-tolyl)ethyl)-pyrrolidinehydrochloride as the starting material. LC-MS: (M+1=422, obsd.=422);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.58 (s, 1H), 7.82 (s, 1H), 7.29 (d,J=12.6 Hz, 2H), 7.12 (d, J=14.5 Hz, 3H), 3.80 (s, 5H), 3.15 (s, 4H),2.95 (s, 1H), 2.66 (s, 3H), 2.49 (t, J=1.7 Hz, 4H), 2.41 (s, 3H), 1.61(s, 4H).

4-(4-(2-(piperidin-1-yl)-1-(o-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A47”)

The title compound was prepared according to the procedure described forthe preparation of A24, using 1-(2-chloro-2-(o-tolyl)ethyl)-piperidinehydrochloride as the starting material. LC-MS: (M+1=436, obsd.=436);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.59 (s, 1H), 7.82 (s, 1H), 7.30 (d,J=10.9 Hz, 2H), 7.14-7.10 (m, 4H), 3.80 (s, 3H), 3.33 (s, 4H), 3.14 (s,5H), 2.51-2.48 (m, 3H), 2.34 (s, 4H), 1.41 (s, 4H), 1.32 (s, 2H).

4-(4-(2-amino)-1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A48”)

The title compound was prepared according to the procedure described forthe preparation of A24, using 2-chloro-2-(3,4-difluorophenyl)-ethanaminehydrochloride as the starting material. LC-MS: (M+1=390, obsd.=390);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.60 (s, 1H), 7.85 (s, 1H), 7.47-7.42(m, 1H), 7.37-7.33 (m, 2H), 7.26 (d, J=31.5 Hz, 1H), 4.09-4.05 (m, 1H),3.82 (s, 2H), 3.22 (s, 6H), 2.50-2.48 (m, 6H).

4-(4-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A49”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(3,4-difluorophenyl)-N,N-dimethyl-ethanamine hydrochloride asthe starting material. LC-MS: (M+1=418, obsd.=418);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.59 (s, 1H), 7.81 (s, 1H), 7.39-7.32(m, 2H), 7.27 (s, 1H), 7.12 (s, 1H), 3.79 (s, 2H), 3.74-3.70 (m, 2H),3.14 (d, J=3.6 Hz, 4H), 2.85-2.80 (m, 1H), 2.50-2.45 (m, 4H), 2.10 (s,6H).

4-(4-(1-(3,4-difluorophenyl)-2-(methylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A50”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(3,4-difluorophenyl)-N-methyl-ethanamine hydrochloride as thestarting material. LC-MS: (M+1=404, obsd.=404);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.61 (s, 1H), 8.28 (s, 1H), 7.85 (s,1H), 7.40-7.30 (m, 3H), 7.19 (s, 1H), 3.82 (s, 2H), 3.68-3.65 (m, 1H),3.23 (s, 4H), 2.66 (t, J=1.8 Hz, 2H), 2.50 (s, 3H), 2.26-2.22 (m, 1H),2.14 (s, 3H).

4-(4-(2-(azetidin-1-yl)-1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A51”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(3,4-difluorophenyl)-ethyl)-azetidine hydrochloride as thestarting material. LC-MS: (M+1=430, obsd.=430);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.97 (s, 1H), 7.40-7.31 (m, 2H), 7.25(s, 1H), 4.06 (s, 4H), 3.54 (s, 1H), 3.45-3.23 (m, 8H), 3.09-3.07 (m,1H), 3.00 (s, 1H), 2.34 (s, 6H).

4-(4-(1-(3,4-difluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A52”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(3,4-difluorophenyl)-ethyl)-pyrrolidine hydrochloride asthe starting material. LC-MS: (M+1=444, obsd.=444);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.74 (s, 1H), 7.25-7.11 (m, 3H), 3.99(s, 2H), 3.66 (s, 1H), 3.11-3.02 (m, 4H), 2.89 (d, J=6.9 Hz, 2H),2.62-2.55 (m, 4H), 2.38 (d, J=7.0 Hz, 4H), 1.63 (d, J=3.5 Hz, 4H).

4-(4-(1-(3,4-difluorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A53”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(3,4-difluorophenyl)-ethyl)-piperidine hydrochloride asthe starting material. LC-MS: (M+1=458, obsd.=458);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.60 (s, 1H), 7.82 (s, 1H), 7.37 (t,J=7.9 Hz, 2H), 7.28 (s, 1H), 7.13 (s, 1H), 3.79 (s, 3H), 3.15 (s, 4H),2.65-2.64 (m, 3H), 2.40 (s, 2H), 2.29 (s, 3H), 1.32 (s, 8H).

4-(4-(1-(3-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A54”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(3-chloro-4-fluorophenyl)-N,N-dimethylethanaminehydrochloride as the starting material. LC-MS: (M+1=432, obsd.=432);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.60 (s, 1H), 7.81 (s, 1H), 7.51-7.49(m, 1H), 7.38-7.30 (m, 1H), 7.29 (t, J=2.0 Hz, 2H), 3.77 (t, J=11.7 Hz,4H), 3.15 (d, J=3.3 Hz, 5H), 2.86 (t, J=12.0 Hz, 1H), 2.50-2.45 (m, 3H),2.12 (s, 6H).

4-(4-(2-(azetidin-1-yl)-1-(3-chloro-4-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A55”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(3-chloro-4-fluorophenyl)-ethyl)-azetidine hydrochlorideas the starting material. LC-MS: (M+1=446, obsd.=446);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.71 (s, 1H), 7.90 (s, 1H), 7.73 (d,J=5.9 Hz, 1H), 7.59-7.51 (m, 5H), 4.81 (s, 1H), 4.09-4.02 (m, 4H), 3.86(s, 2H), 3.04 (s, 4H), 2.75 (s, 2H), 2.50-2.48 (m, 2H), 2.32-2.26 (m,2H).

4-(4-(1-(3-chloro-4-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A56”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(3-chloro-4-fluorophenyl)-ethyl)-pyrrolidine hydrochlorideas the starting material. LC-MS: (M+1=460, obsd.=460);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.12 (s, 1H), 7.48-7.45 (m, 1H),7.31-7.22 (m, 2H), 3.99 (s, 2H), 3.83 (s, 1H), 3.04 (q, J=6.9 Hz, 1H),2.65-2.57 (m, 8H), 1.81 (s, 4H), 1.41 (s, 1H).

4-(4-(1-(3-chloro-4-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A57”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(3-chloro-4-fluorophenyl)-ethyl)-piperidine hydrochlorideas the starting material. LC-MS: (M+1=474, obsd.=474);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.59 (s, 1H), 7.81 (s, 1H), 7.50 (dd,J=1.5, 7.3 Hz, 1H), 7.38-7.27 (m, 3H), 3.76 (t, J=11.1 Hz, 3H), 3.15 (s,4H), 2.72 (d, J=8.5 Hz, 1H), 2.66 (s, 1H), 2.50-2.48 (m, 5H), 2.40 (s,2H), 1.36-1.32 (m, 6H), 1.23 (s, 1H).

4-(4-(1-(4-chloro-3-fluorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A58”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-chloro-3-fluorophenyl)-N,N-dimethylethanaminehydrochloride as the starting material. LC-MS: (M+1=432, obsd.=432);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 9.60 (s, 1H), 7.82 (s, 1H), 7.53 (d,J=6.8 Hz, 1H), 7.37 (d, J=10.3 Hz, 2H), 7.15 (d, J=7.2 Hz, 1H), 3.79 (s,3H), 3.15 (s, 4H), 2.68 (s, 1H), 2.49 (s, 1H), 2.22 (s, 4H), 2.08 (s,6H).

4-(4-(1-(4-chloro-3-fluorophenyl)-2-(methylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A59”)

The title compound was prepared according to the procedure described forthe preparation of A24, using2-chloro-2-(4-chloro-3-fluorophenyl)-N-methyl-ethanamine hydrochlorideas the starting material. LC-MS: (M+1=420, obsd.=420);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.91 (d, J=3.1 Hz, 1H), 7.72 (d,J=8.1 Hz, 1H), 7.69-7.61 (m, 1H), 7.42-7.40 (m, 1H), 4.63 (s, 1H), 3.88(s, 2H), 3.70 (s, 1H), 3.36 (s, 4H), 3.23 (s, 1H), 2.93 (s, 3H),2.50-2.49 (m, 2H), 2.41 (s, 3H).

4-(4-(2-(azetidin-1-yl)-1-(4-chloro-3-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A60”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(4-chloro-3-fluorophenyl)-ethyl)-azetidine hydrochlorideas the starting material. LC-MS: (M+1=446, obsd.=446);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 8.28 (s, 2H), 7.80 (s, 1H), 7.49 (t,J=8.1 Hz, 1H), 7.30 (dd, J=1.7, 10.5 Hz, 1H), 7.17 (dd, J=1.4, 8.3 Hz,1H), 3.80 (d, J=9.9 Hz, 2H), 3.60 (t, J=6.2 Hz, 1H), 3.22 (d, J=6.9 Hz,2H), 3.19-3.07 (m, 6H), 2.49 (t, J=1.8 Hz, 3H), 2.41-2.29 (m, 3H), 1.97(s, 2H).

4-(4-(1-(4-chloro-3-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A61”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(4-chloro-3-fluorophenyl)-ethyl)-pyrrolidine hydrochlorideas the starting material. LC-MS: (M+1=460, obsd.=460);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.70 (s, 1H), 7.44 (t, J=8.0 Hz, 1H),7.12 (dd, J=1.8, 10.1 Hz, 1H), 7.01 (t, J=8.2 Hz, 1H), 4.00-3.99 (m,3H), 3.80 (t, J=12.6 Hz, 1H), 3.38 (dd, J=6.4, 13.0 Hz, 1H), 3.29 (s,4H), 3.22 (s, 4H), 2.56-2.40 (m, 4H), 1.93 (s, 4H).

4-(4-(1-(4-chloro-3-fluorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A62”)

The title compound was prepared according to the procedure described forthe preparation of A24, using1-(2-chloro-2-(4-chloro-3-fluorophenyl)-ethyl)-piperidine hydrochlorideas the starting material. LC-MS: (M+1=474, obsd.=474);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: 7.79 (s, 1H), 7.49 (t, J=8.0 Hz, 1H),7.30 (dd, J=1.4, 10.7 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 3.79 (s, 3H),3.15 (s, 4H), 2.50-2.49 (m, 7H), 2.44 (s, 2H), 1.32 (d, J=21.6 Hz, 6H).

4-(4-(2((2-(dimethylamino)ethyl)amino)-1-(4-(trifluoromethyl)phenyl)-ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A63”)

The title compound was prepared according to the procedure described forthe preparation of A24, usingN¹-(2-chloro-2-(4-(trifluoromethyl)phenyl)ethyl)-N²,N²-dimethylethane-1,2-diaminehydrochloride as the starting material. LC-MS: (M+1=493, obsd.=493);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: δ 8.33 (s, 1H), 7.77 (s, 1H), 7.64(d, J=8.1 Hz, 2H), 7.46 (d, J=8.0 Hz, 2H), 4.00-3.94 (m, 4H), 3.16 (s,5H), 2.98-2.89 (m, 5H), 2.74-2.51 (m, 11H).

4-(4-(2-((2-(dimethylamino)ethyl)amino)-1-(3-(trifluoromethyl)phenyl)-ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A64”)

The title compound was prepared according to the procedure described forthe preparation of A24, usingN¹-(2-chloro-2-(3-(trifluoromethyl)phenyl)ethyl)-N²,N²-dimethylethane-1,2-diaminehydrochloride as the starting material. LC-MS: (M+1=493, obsd.=493);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: δ 9.63 (s, 1H), 8.19 (s, 1H), 7.86(s, 1H), 7.73-7.61 (m, 2H), 7.59-7.53 (m, 2H), 7.31 (s, 1H), 3.94-3.90(m, 1H), 3.83 (s, 2H), 3.23 (s, 4H), 2.67-2.63 (m, 2H), 2.54-2.41 (m,6H), 2.39-2.28 (m, 8H).

4-(4-(2-((2-(dimethylamino)ethyl)amino)-1-(p-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A65”)

The title compound was prepared according to the procedure described forthe preparation of A24, usingN¹-(2-chloro-2-(p-tolyl)phenyl)-ethyl)-N²,N²-dimethylethane-1,2-diaminehydrochloride as the starting material. LC-MS: (M+1=439, obsd.=439);

¹H NMR (400 MHz, DMSO-d₆) δ [ppm]: δ 9.62 (s, 1H), 8.14 (s, 1H), 7.86(s, 1H), 7.29 (t, J=8.4 Hz, 3H), 7.15 (d, J=7.9 Hz, 2H), 3.90 (s, 1H),3.83 (s, 2H), 3.16 (s, 5H), 2.72 (s, 4H), 2.50-2.48 (m, 3H), 2.29 (d,J=6.56 Hz, 11H).

Biological Activity

The IC₅₀ values reported for the compounds in the Experimental sectionwere derived from the following protocol for the p70S6K and AKT enzymeassays.

P70S6K Enzyme Assay

P70S6K inhibitor compounds were diluted and plated in 96 well plates. Areaction mixture including the following components was then added tothe compound plate to initiate the enzyme reaction; P70S6K (3 nM, T412Emutant, Millipore) was mixed with 24 μM ATP in an assay buffercontaining 100 mM Hepes (pH 7.5), 5 mM MgCl2, 1 mM DTT, 0.015% Brij and1 μM of the substrate peptide FITC-AHA-AKRRRLSSLRA-OH (derived from theS6 ribosomal protein sequence, FITC=fluorescein isothiocyanate,AHA=6-aminohexanoic acid). The reaction was incubated for 90 min at 25°C., before the addition of 10 mM EDTA to stop the reaction. Theproportion of substrate and product (phosphorylated) peptide wasanalysed on a Caliper Life Sciences Lab Chip 3000, using a pressure of−1.4 psi, and upstream and downstream voltages of −3000 and −700respectively. Product peaks were resolved before substrate peaks on theresulting chromatograms.

The values for the p70S6K enzyme inhibition assay for selected compoundsset out in the Experimental section are presented in Table 1 presentfunctional data for selected compounds described by the presentinvention.

AKT Enzyme Assay

A TTP Mosquito liquid handling instrument was used to place 125 nl ofthe appropriate concentration of inhibitor in 100% DMSO (for a doseresponse curve calculation) into each well of a 384-well plate. To thisreaction components were added to a final volume of 12.5 μl:

-   -   0.1 ng/μl His-AKT (Full Length), (Invitrogen, Part # P2999, Lot        #641228C).    -   160 uM ATP (Fluka, 02055)    -   1 mM DTT (Sigma, D0632)    -   1 mM MgCl2 (Sigma, M1028)    -   1 μM substrate peptide (sequence FITC-AHA-GRPRTSSFAEG-NH2),    -   synthesized by Tufts Peptide Synthesis service.    -   100 mM HEPES pH 7.5 (Calbiochem, 391338)    -   0.015% Brij-35 (Sigma, B4184)

The reaction was incubated for 90 min at 25° C., and then stopped by theaddition of 70 μl of Stop buffer (100 mM HEPES pH 7.5, 0.015% Brij-35,10 mM EDTA (Sigma, E7889)).

The plate was read on a Caliper LC 3000 in an Off-Chip mobility shiftassay format, using the following parameters for a 12-sipper chip:screening pressure −2.3 psi, upstream voltage −500, and downstreamvoltage −3000. These conditions caused unphosphorylated substrate andphosphorylated product peptide to resolve as separate peaks allowingdirect measurement of percentage of conversion of substrate to product.The percent conversion was plotted against concentration of inhibitor toproduce a sigmoidal dose response curve, from which an IC50 wascalculated.

The values for the p70S6K and AKT enzyme inhibition assays for selectedcompounds set out in the Experimental section are presented in Table 1.The data are presented as follows:

+++++: <25 nM;++++: 25-100 nM;+++: 101 nM-500 nM;++: 501 nM-1000 nM;

+: >1 μM.

TABLE 1 p70S6K Enzyme Inhibition by Compounds Described by Formula (I)Compound IC₅₀ p70S6K IC₅₀ AKT No. (nM) (nM) A1 ++++ +++ A2 ++++ ++++A3 + + A4 + +++ A5 + +++ A6 +++ +++ A7 +++ +++ A8 +++ ++++ A9 ++++ ++++A10 ++ +++ A11 ++ +++ A12 ++ +++ A13 ++++ +++ A14 ++ ++ A15 +++ +++ A16++++ ++++ A17 +++ ++++ A18 +++ ++++ A19 ++++ ++++ A20 +++ ++++ A21 + ++A22 +++ ++++ A23 + + A24 + + A25 + + A26 ++ +++ A27 + + A28 ++ +++A29 + + A30 ++ ++ A31 + + A32 + ++ A33 + ++ A34 + + A35 + + A36 + +A37 + + A38 + + A39 + + A40 + + A41 + + A42 + + A43 + + A44 + + A45 + +A46 + + A47 + + A48 + + A49 + + A50 + + A51 + + A52 + + A53 + + A54 + +A55 + + A56 + + A57 + + A58 + +++ A59 + + A60 + + A61 + +++ A62 + ++A63 + + A64 + + A65 + +

The following examples relate to medicaments:

Example A Injection Vials

A solution of 100 g of an active ingredient of the formula I and 5 g ofdisodium hydrogenphosphate in 3 l of bidistilled water is adjusted to pH6.5 using 2 N hydrochloric acid, sterile filtered, transferred intoinjection vials, lyophilised under sterile conditions and sealed understerile conditions. Each injection vial contains 5 mg of activeingredient.

Example B Suppositories

A mixture of 20 g of an active ingredient of the formula I with 100 g ofsoya lecithin and 1400 g of cocoa butter is melted, poured into mouldsand allowed to cool. Each suppository contains 20 mg of activeingredient.

Example C Solution

A solution is prepared from 1 g of an active ingredient of the formulaI, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g of Na₂HPO₄.12H₂O 2O and 0.1 g ofbenzalkonium chloride in 940 ml of bidistilled water. The pH is adjustedto 6.8, and the solution is made up to 1 l and sterilised byirradiation. This solution can be used in the form of eye drops.

Example D Ointment

500 mg of an active ingredient of the formula I are mixed with 99.5 g ofVaseline under aseptic conditions.

Example E Tablets

A mixture of 1 kg of active ingredient of the formula I, 4 kg oflactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesiumstearate is pressed in a conventional manner to give tablets in such away that each tablet contains 10 mg of active ingredient.

Example F Dragees

Tablets are pressed analogously to Example E and subsequently coated ina conventional manner with a coating of sucrose, potato starch, talc,tragacanth and dye.

Example G Capsules

2 kg of active ingredient of the formula I are introduced into hardgelatine capsules in a conventional manner in such a way that eachcapsule contains 20 mg of the active ingredient.

Example H Ampoules

A solution of 1 kg of active ingredient of the formula I in 60 l ofbidistilled water is sterile filtered, transferred into ampoules,lyophilised under sterile conditions and sealed under sterileconditions. Each ampoule contains 10 mg of active ingredient.

1. A compound of formula (I),

or a pharmaceutically acceptable salt, solvate, solvate of salts,tautomer or stereoisomer, including a mixture thereof in all ratiosthereof, wherein: X¹ is N or CH, X² is CH₂ or NH, X³ is CO, X⁴ is O, CH₂or NH, W is N or CH, R¹ is Ar or Het, R² is [C(R³)₂]_(p)Het¹ or[C(R³)₂]_(p)N(R³)₂, each R³ is independently H or alkyl with 1, 2, 3, or4 C-atoms, which is optionally substituted; Ar is phenyl which isunsubstituted or mono-, di- or trisubstituted by Hal, A, phenyl,CON(R³)₂, COOR³, NHCOA, NHSO₂A, CHO, COA, SO₂N(R³)₂, SO₂A,[C(R³)₂]_(p)OR³, [C(R³)₂]_(p)N(R³)₂ and/or [C(R³)₂]_(p)CN, Het is furyl,thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl,pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolylor quinolyl, which is unsubstituted or mono-, di- or trisubstituted byHal, A, [C(R³)₂]_(p)OR³, [C(R³)₂]_(p)N(R³)₂, NO₂, CN, [C(R³)₂]_(p)COOR³,CON(R³)₂, NR³COA, NR³SO₂A, SO₂N(R³)₂, S(O)_(m)A and/orO[C(R³)₂]_(q)N(R³)₂, Het¹ is dihydropyrrolyl, pyrrolidinyl, azetidinyl,oxetanyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl,tetrahydrofuranyl, dihydropyridyl, tetrahydropyridyl, piperidinyl,azepanyl, morpholinyl, hexahydropyridazinyl, hexahydropyrimidinyl,[1,3]dioxolanyl, tetrahydropyranyl, pyridyl or piperazinyl, which isunsubstituted or mono- or disubstituted by A, each A is independentlyunbranched or branched alkyl with 1-10 C-atoms, wherein one or twonon-adjacent CH- and/or CH₂-groups may be replaced by N-, O- and/orS-atoms and wherein 1-7 H-atoms may be replaced by F or Cl, each Hal isindependently F, Cl, Br or I, each m is independently 0, 1 or 2, each nis independently 0, 1 or 2, each p is independently 0, 1, 2, 3 or 4,each q is independently 2, 3 or
 4. 2. The compound according to claim 1,or a pharmaceutically acceptable salt, solvate, solvate of salts,tautomer or stereoisomer, including a mixture thereof in all ratiosthereof, wherein: X¹ is N or CH, X² is CH₂ or NH, X³ is CO, X⁴ is CH₂ orNH, W is N or CH, R¹ is Ar, R² is [C(R³)₂]_(p)Het¹ or[C(R³)₂]_(p)N(R³)₂, each R³ is independently H or methyl, Ar is phenylwhich is unsubstituted or mono- or disubstituted by Hal and/or A, Het¹is pyrrolidinyl, azetidinyl or piperidinyl, each A is independentlyunbranched or branched alkyl with 1-10 C-atoms, wherein one or twonon-adjacent CH- and/or CH₂-groups may be replaced by N- and/or O-atomsand wherein 1-7 H-atoms may be replaced by F or Cl, or Cyc, Cyc iscyclic alkyl with 3-7 C-atoms, Hal is F, Cl, Br or I, each n isindependently 0 or 1, each p is independently 0, 1, 2, 3 or
 4. 3. Thecompound according to claim 1, or a pharmaceutically acceptable salt,solvate, solvate of salts, tautomer or stereoisomer, including a mixturethereof in all ratios thereof, selected from the group:4-{4-[2-dimethylamino-1-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A24”)4-{4-[2-dimethylamino-1-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A25”)4-{4-[2-dimethylamino-1-(4-chloro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A26”)4-{4-[2-dimethylamino-1-(3-chloro-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A27”)4-{4-[2-dimethylamino-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A28”)4-{4-[1-(4-fluoro-phenyl)-2-(pyrrolidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A29”)4-{4-[1-(4-chloro-phenyl)-2-(pyrrolidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A30”)4-{4-[1-(4-fluoro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A31”)4-{4-[1-(4-chloro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A32”)4-{4-[1-(4-trifluoro-phenyl)-2-(piperidin-yl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A33”)4-{4-[2-Pyrrolidin-1-yl-1-(4-trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl}-7,8-dihydro-5H-pteridin-6-one(“A34”)4-(4-(1-(2-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one (“A35”)4-(4-(2-(dimethylamino)-1-(2-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one (“A36”)4-(4-(2-(azetidin-1-yl)-1-(2-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A37”)4-(4-(1-(2-fluorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A38”)4-(4-(2-amino-1-(2-chlorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A39”)4-(4-(1-(2-chlorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A40”)4-(4-(1-(2-chlorophenyl)-2-(methylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A41”)4-(4-(2-(azetidin-1-yl)-1-(2-chlorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A42”)4-(4-(1-(2-chlorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A43”)4-(4-(1-(2-chlorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A44”)4-(4-(2-(dimethylamino)-1-(o-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A45”)4-(4-(2-(pyrrolidin-1-yl)-1-(o-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A46”)4-(4-(2-(piperidin-1-yl)-1-(o-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A47”)4-(4-(2-amino)-1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A48”)4-(4-(1-(3,4-difluorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A49”)4-(4-(1-(3,4-difluorophenyl)-2-(methylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A50”)4-(4-(2-(azetidin-1-yl)-1-(3,4-difluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A51”)4-(4-(1-(3,4-difluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A52”)4-(4-(1-(3,4-difluorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A53”)4-(4-(1-(3-chloro-4-fluorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A54”)4-(4-(2-(azetidin-1-yl)-1-(3-chloro-4-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A55”)4-(4-(1-(3-chloro-4-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A56”)4-(4-(1-(3-chloro-4-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A57”)4-(4-(1-(4-chloro-3-fluorophenyl)-2-(dimethylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A58”)4-(4-(1-(4-chloro-3-fluorophenyl)-2-(methylamino)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A59”)4-(4-(2-(azetidin-1-yl)-1-(4-chloro-3-fluorophenyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A60”)4-(4-(1-(4-chloro-3-fluorophenyl)-2-(pyrrolidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A61”)4-(4-(1-(4-chloro-3-fluorophenyl)-2-(piperidin-1-yl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A62”)4-(4-(2((2-(dimethylamino)ethyl)amino)-1-(4-(trifluoromethyl)phenyl)-ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A63”)4-(4-(2-((2-(dimethylamino)ethyl)amino)-1-(3-(trifluoromethyl)phenyl)-ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A64”) and4-(4-(2-((2-(dimethylamino)ethyl)amino)-1-(p-tolyl)ethyl)piperazin-1-yl)-7,8-dihydropteridin-6(5H)-one(“A65”).
 4. A process for the preparation of compounds of claim 1 andpharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof, comprising: a) reacting a compound of formula (II)

wherein X¹ is N or CH, X² is CH₂ or NH, X³ is CO, X⁴ is O, CH₂ or NH,with a compound of formula (III)

wherein W is N or CH, R¹ is Ar or Het, R² is [C(R³)₂]_(p)Het¹ or[C(R³)₂]_(p)N(R³)₂, or b) for the preparation of a compound of claim 1,wherein X³ is CO and X⁴ is NH, a compound of formula (IV)

wherein X¹ is N or CH, X² is CH₂ or NH, X³ is CO, X⁴ is O, CH₂ or NH, Wis N or CH, R¹ is Ar or Het, R² is [C(R³)₂]_(p)Het¹ or[C(R³)₂]_(p)N(R³)², and A′ is alkyl with 1, 2, 3 or 4 C-atoms, iscyclised, and/or a base or acid of the compound of claim 1 is convertedinto one of its salts.
 5. A pharmaceutical composition comprising atleast one compound of claim 1 and/or pharmaceutically acceptable salts,solvates, solvates of salts, tautomers or stereoisomers, includingmixtures thereof in all ratios thereof, and optionally anpharmaceutically acceptable carrier, excipient or vehicle.
 6. A methodof treating cancer, comprising administering to a subject a compound ofclaim 1 and/or pharmaceutically acceptable salts, solvates, solvates ofsalts, tautomers or stereoisomers, including mixtures thereof in allratios thereof.
 7. A method of treating tumors, comprising administeringto a subject a therapeutically effective amount of a compound of claim1, and/or pharmaceutically acceptable salts, solvates, solvates ofsalts, tautomers or stereoisomers, including mixtures thereof in allratios thereof, where the therapeutically effective amount of thecompound of claim 1 is administered in combination with radiotherapy anda cytotoxic agent or antiproliferative agent.
 8. A method of treatingcancer, septic shock, Primary open Angle Glaucoma (POAG), hyperplasia,rheumatoid arthritis, psoriasis, artherosclerosis, retinopathy,osteoarthritis, endometriosis, chronic inflammation, and/orneurodegenerative diseases, comprising administering to a subject thecompound of claim 1 and/or pharmaceutically acceptable salts, solvates,solvates of salts, tautomers or stereoisomers, including mixturesthereof in all ratios thereof.
 9. A method of treating tumors,comprising administering to a subject a therapeutically effective amountof the compound of claim 1, and/or pharmaceutically acceptable salts,solvates, solvates of salts, tautomers or stereoisomers, includingmixtures thereof in all ratios thereof, wherein the therapeuticallyeffective amount of the compound of claim 1 is administered incombination with a compound selected from: 1) oestrogen receptormodulator, 2) androgen receptor modulator, 3) retinoid receptormodulator, 4) cytotoxic agent, 5) antiproliferative agent, 6)prenyl-protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8)HIV protease inhibitor, 9) reverse transcriptase inhibitor and 10)further angiogenesis inhibitors.
 10. A kit consisting of separate packsof (a) an effective amount of a compound of claim 1 and/orpharmaceutically acceptable salts, solvates, solvates of salts,tautomers or stereoisomers, including mixtures thereof in all ratiosthereof, and (b) an effective amount of a further medicament activeingredient.
 11. The compound of claim 1, wherein R³ is H or methyl. 12.The compound of claim 1, wherein Ar is phenyl which is unsubstituted ormono- or disubstituted by Hal and/or A.
 13. The compound of claim 1,wherein Het is pyridyl or pyrimidyl, which is unsubstituted ormonosubstituted by A.
 14. The compound of claim 1, wherein Het¹ ispyrrolidinyl, azetidinyl or piperidinyl.
 15. The compound of claim 1,wherein R¹ is


16. The compound of claim 1, wherein R² is


17. The compound of claim 1, of formula I-h:

or a pharmaceutically acceptable salt, solvate, solvate of salt,tautomer or stereoisomer, including a mixture thereof in all ratiosthereof.